Comment by Peter Davies —Posted 6 July 2001
I don't see anything in the references given that suggests that AD
pathology - neuritic plaques and neurofibrillary tangles in BOTH
hippocampus and neocortex - occur with any substantial frequency in
elderly patients with schizophrenia. The Bayer reference finds
microglial activation in 3 of 14 schizophrenics, but the ages of the
individual patients was not given. HLA-DR reactivity is certainly not a
reliable indicator of AD pathology (1).
My point is solely concerned
with the pathologic hallmarks of AD: I am not arguing that elderly
schizophrenics do not show signs of cognitive impairment: many appear to
do so (2). However, I am not aware of post mortem studies of a
substantial series of elderly
schizophrenics that fails to show lower frequency of AD lesions than in
the general population.
1. Mattiace LA, Davies P, Dickson DW. Detection of HLA-DR on microglia in the human brain is a function of both clinical and technical factors. Am J Pathol. 1990 May 1;136(5):1101-14. Abstract
2. Powchik P, Davidson M, Nemeroff CB, Haroutunian V, Purohit D, Losonczy M, Bissette G, Perl D, Ghanbari H, Miller B. Alzheimer's-disease-related protein in geriatric schizophrenic patients with cognitive impairment. Am J Psychiatry. 1993 Nov 1;150(11):1726-7. Abstract
Comment by Ratan Bhat —Posted 25 July 2001
I was reading your comment on Peter Davies's observation with interest -
that the brains of people with schizophrenia have never been reported to
show any Alzheimer pathology. If this is true, I would like to suggest a
common molecular target having opposing expression patterns between the two
neuronal disorders. As you know the Ser/Thr kinase GSK3b has been implicated
in the tau pathology of AD. Both, levels of GSK3b and the active site
phsophorylation have been shown to be increased in AD brain (pre-tangles and
tangles) by Kahlid Iqbal and Richard Cowburn's groups.
Furthermore, Jesus Avila's group has recently demonstrated that inducible GSK3b adult transgenic mice develop pre-tangle pathology and neuronal degeneration. In
contrast to AD, GSK3b immunoreactivity is decreased in schizophrenic brains.
It is unclear whether or not this results in schizophrenia or is a unique
developmental effect. However, since GSK3b is low in schizopheric brain
tissue but is increased in AD brain, it raises the intriguing possibility
that GSK3b or its signalling partners could be a common interfering
molecular mechanism between AD and schizophrenia.
References:
Pei JJ, Tanaka T, Tung YC, Braak E, Iqbal K, Grundke-Iqbal I. Distribution, levels, and activity of glycogen synthase kinase-3 in the Alzheimer disease brain. J Neuropathol Exp Neurol. 1997 Jan;56(1):70-8. Abstract
Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn RF. Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. J Neuropathol Exp Neurol. 1999 Sep 1;58(9):1010-9. Abstract
Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J. 2001 Jan 15;20(1-2):27-39. Abstract
Beasley C, Cotter D, Khan N, Pollard C, Sheppard P, Varndell I, Lovestone S, Anderton B, Everall I. Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia. Neurosci Lett. 2001 Apr 20;302(2-3):117-20. Abstract
Kozlovsky N, Belmaker RH, Agam G. Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. Am J Psychiatry. 2000 May 1;157(5):831-3. Abstract
—Ratan Bhat, Ph.D
Other Roles of AbPP, Presenilin and Ab Peptide
Growth or No Growth: APP Weighs the Question
Angela Biggs Proposes a Biological Function for APP
First, consider the two forms of APP. The membrane AβPP form has a receptor-like protease(1) with a cytoplasmic region capable of binding small G-proteins.(2) In neurons, the membrane form is found at the synaptic zone at the tip of growth.(3,4) The secreted form of APP is an extracellular protease that has been shown to stimulate neurite extension.
Now consider that AβPP is also known as protease nexin II, a serine protease.(5,6,7) The serine protease inhibitor neuroserpin has been shown in PC12 cells not only to decrease the length of neural axon extensions, but also to stop axon growth altogether.(11)
I propose that the biological function of APP appears to be to act as a serine protease to "switch" neurons into the growth mode.
To weigh this idea, discoveries in other cell types should be considered: Maspins are serine protease inhibitors that insert into the membrane and control the cytoskeleton; without maspins, breast cancer cells metastasize.(8)
Next, consider that P53 turns on maspin expression by binding DNA.(9) Note that p53 binding is also required for bcl-2 expression. In neurons, AβPP seems to prevent p53 from binding to DNA.(10) So serpins and serine proteases have opposite relationships with P53. This makes sense because p53 binding protects quiescent neurons from apoptosis via bcl-2, while rapidly growing neurons could be easily eliminated if needed.(14)
Neuroserpins and α-1-antichymotrypsin (α-1-ACT) are serine protease inhibitors that could be acting as maspins. Interestingly, expression of APP and α-1-ACT have been shown to coexist together in the membrane of human skeletal muscle.(12)—a serine protease receptor with a serine protease inhibitor receptor.
Putting it all together, there seem to be two critical states of neurons: those that are growing and using serine proteases to do so, and those that are quiescent. Growing neurons would be using APP pathways, possibly through RhoG (a small G-protein) to extend microtubules, whereas quiescent neurons would use the membrane serpin. I speculate that serpins may act through RhoA to dictate a non-growth cytoskeletal structure.(13)
APP and Cholesterol
Another nice feature of this proposed APP function as a controller of "growth of non-growth" is that it explains the cholesterol relationship. The elongated membrane of the nerve growth cone would require more cholesterol in the membrane for structural stability. Simple membrane structures require less cholesterol, while complex membrane structures require more. The addition of cholesterol to membranes stabilizes the lipids, thus preventing them from floating away.(15) If the body wanted to get rid of cholesterol, it might attempt to use as much as possible in complex membranes like those of growing axons and growth cones.
For example, treating APP-transfected HEK cells with statin drugs reduced the processing of newly synthesized APP. Adding cholesterol to the HEK cells increased BACE cleavage of APP by fourfold.(16) The cells appear to choose the APP pathway in order to use cholesterol in the membrane!
What about the decrease of the α-secretase processing of APP? My understanding is that there are two main types of APP cleavage, α and β. Transgenic mice overexpressing APP when exposed to high cholesterol show an increase of the β-secretase cleavage of APP and a decrease of α-secretase cleavage.(17) Since α-secretase cleavage occurs at the membrane surface of neurons,(18) I suggest that this α cleavage might be an "off cleavage." Could it also be that neuroserpin inhibits APP, then the secretase cleaves it, turning the growth mode of the APP receptor off permanently, then stimulating the nerves nearby as if to take turns growing?
I reason that high cholesterol would push neurons into the APP cytoskeleton growing mode, which uses cholesterol in the membrane. Problems could occur once the neuron could no longer keep up the growing pace, or too much Aβ was made due to high cholesterol stimulating APP production. If the nerve became stuck in the growth mode, it makes sense that proteins used in growth could pile up; this includes APP, tau,(21) and α-synuclein as a plasma membrane omega fatty acid transporter.(22)
APP and Dementia
Another appealing feature of APP functioning as a serine protease and the neuron switching into a growth mode is that it might also help explain dementia and the neuron's mitochondria. Assuming that the mitochondria must be coordinated with neuron growth and division, it is interesting to note that the transmembrane protease called rhomboid responsible for the proteolysis of mitochondrial membranes is a serine protease.(19) So a serine protease in mitochondrial membranes appears to remodel the mitochondria from the mesh system into "portable, hotdog-like" organelles. I am suggesting that when APP, a plasma membrane serine protease receptor, switches the neuron to a growth mode, somehow a serine protease in the mitochondrial membrane is also switched on.
Where does this line of thought lead? Mitochondria have been called the "memory" of neurons, as they use their calcium stores to record stimulation and adjust neurotransmitter release based on stimulation.(20) Wouldn't it be interesting if the morphology of the mitochondria affected this calcium memory property? For instance, if the mitochondria are in the mesh form, the neuron can "remember," but when mitochondria are in the hot dog form during serine protease expression, the neuron cannot. This is, in effect, a speculation that sudden returnable memory relates to the state of the mitochondria. It is unknown whether the APP serine protease in the plasma membrane is coordinated with the mitochondrial serine protease, but the fact that they are both transmembrane serine proteases is suggestive. Could APP trigger dementia by causing the mitochondrial serine protease to be expressed?
Consider resveratrol, the polyphenolic compound of red wine, cranberries, and blueberries. Resveratrol has been found to slow the growth of prostate cancer cells.(23) Serine protease inhibitors—the serpins—use their phenol groups to inhibit the serine proteases. Could the return of memory that occurs with blueberries and other resveratrol-containing foods actually be due to resveratrol acting like a serpin, thus inhibiting the serine protease of the mitochondria and allowing the mitochondria to form back into a mesh?
There are a lot of possibilities with this growth model of APP as a serine protease. I hope enterprising scientists will take up testing it! —Angela Biggs, Independent Researcher.
Please note: Just in case it is not mentioned in the live discussion, I would like
to note that clioquinol is an antifungal and it is not entirely
understood how it is working in Alzheimer's patients.
References:
1. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19-25;325(6106):733-6. Abstract
2. Nishimoto I, Okamoto T, Matsuura Y, Takahashi S, Okamoto T, Murayama Y, Ogata E. Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o)
Nature. 1993 Mar 4;362(6415):75-9. Abstract
3. Schubert D. The possible role of adhesion in synaptic modification. Trends Neurosci. 1991 Apr;14(4):127-30. Review. No abstract available. Abstract
4. Levitan and Kaczmarek. 1991. The Neuron. pp 343-344.
5. Qiu WQ, Ferreira A, Miller C, Koo EH, Selkoe DJ. Cell-surface beta-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner. J Neurosci. 1995 Mar;15(3 Pt 2):2157-67. Abstract
6. Jin LW, Ninomiya H, Roch JM, Schubert D, Masliah E, Otero DA, Saitoh T. Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J Neurosci. 1994 Sep;14(9):5461-70. Abstract
7. Oltersdorf T, Fritz LC, Schenk DB, Lieberburg I, Johnson-Wood KL, Beattie EC, Ward PJ, Blacher RW, Dovey HF, Sinha S. The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II. Nature. 1989 Sep 14;341(6238):144-7. Abstract
8. Sheng S, Carey J, Seftor EA, Dias L, Hendrix MJ, Sager R. Maspin acts at the cell membrane to inhibit invasion and motility of mammary and prostatic cancer cells. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11669-74. Abstract
9. Zou Z, Gao C, Nagaich AK, Connell T, Saito S, Moul JW, Seth P, Appella E, Srivastava S. p53 regulates the expression of the tumor suppressor gene maspin. J Biol Chem. 2000 Mar 3;275(9):6051-4. Abstract
10. Xu X, Yang D, Wyss-Coray T, Yan J, Gan L, Sun Y, Mucke L. Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis.
Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7547-52. Abstract
11. Parmar PK, Coates LC, Pearson JF, Hill RM, Birch NP. Neuroserpin regulates neurite outgrowth in nerve growth factor-treated PC12 cells. J Neurochem. 2002 Sep;82(6):1406-15.
Abstract
12. Akaaboune M, Ma J, Festoff BW, Greenberg BD, Hantai D. Neurotrophic regulation of mouse muscle beta-amyloid protein precursor and alpha 1-antichymotrypsin as revealed by axotomy. J Neurobiol. 1994 May;25(5):503-14. Abstract and Akaaboune M, Verdiere-Sahuque M, Lachkar S, Festoff BW, Hantai D. Serine proteinase inhibitors in human skeletal muscle: expression of beta-amyloid protein precursor and alpha 1-antichymotrypsin in vivo and during myogenesis in vitro. J Cell Physiol. 1995 Dec;165(3):503-11. Abstract
13. Vignal E, Blangy A, Martin M, Gauthier-Rouviere C, Fort P. Kinectin is a key effector of RhoG microtubule-dependent cellular activity. Mol Cell Biol. 2001 Dec;21(23):8022-34. Abstract
14. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - the p53 network. J Cell Sci. 2003 Oct 15;116(Pt 20):4077-85. Abstract
15. Alberts et al. 1989. Molecular Biology of the Cell, 2nd edition. pp 279.
16. Frears ER, Stephens DJ, Walters CE, Davies H, Austen BM. The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport. 1999 Jun 3;10(8):1699-705. Abstract
17. Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000 Aug;7(4):321-31. Erratum in: Neurobiol Dis 2000 Dec;7(6 Pt B):690. Abstract
18. Parvathy S, Hussain I, Karran EH, Turner AJ, Hooper NM. Cleavage of Alzheimer's amyloid precursor protein by alpha-secretase occurs at the surface of neuronal cells.
Biochemistry. 1999 Jul 27;38(30):9728-34. Abstract
19. McQuibban GA, Saurya S, Freeman M. Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature. 2003 May 29;423(6939):537-41. Abstract
20. Kaczmarek LK. Mitochondrial memory banks. Calcium stores keep a record of neuronal stimulation. J Gen Physiol. 2000 Mar;115(3):347-50. Review. No abstract available. Abstract
21. Fan QW, Yu W, Senda T, Yanagisawa K, Michikawa M. Cholesterol-dependent modulation of tau phosphorylation in cultured neurons. J Neurochem. 2001 Jan;76(2):391-400. Abstract
22. Pro Natl. Acad Sci USA 98 (16):9110-5.
23. Mitchell SH, Zhu W, Young CY. Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res. 1999 Dec 1;59(23):5892-5. Abstract
Comment by Barry W. Festoff—Posted 19 December 2004
Angela Biggs refers to the protease nexin II form of AbetaAPP as a
serine protease. Although her discussion and hypotheses are quite
interesting, this is incorrect. It is a serine protease inhibitor, and
not of the serpin class as originally conceived of by Dennis Cunnigham's
group at UC, Irvine.
It is in fact a kunin-type serine protease inhibitor, actually a
bikunin.
Comment by Angela Biggs—Posted 18 April 2005
Before we start dividing serine protease inhibitors up into groups we
should look at the serine protease inhibitor family. Consider that
they have been conserved in evolution and exist in not only eukaryotes
but prokaryotes, thus they must serve a very important purpose. I am
suggesting that serine protease inhibitors/ serine proteases are growth
keys and thus a critical step in the evolution of single cells. I am
merely suggesting a short cut by looking at the "big picture," the
entire family of serine protease inhibitors, we may be enlightened and
see the function of individual family members.
See: http://mbe.oupjournals.org/cgi/reprint/19/11/1881
Comment by Ole Isacson—Posted 18 June 2005
I am pleased to find a posting by Angela Biggs with some reference to the synaptic-dendritic growth regulation hypothesis. The idea of a continuous dynamic growth-regulation disturbance (as a pathological synaptic mechanism) as the degenerative process in AD and Down syndrome is interesting. We started to investigate this hypothesis in vivo a few years ago by evaluating clues about growth-dynamics of the cholinergic synapse in hippocampus—and could clearly show a number of interactions that suggest that the APPs and Aβ regulation partly depend on normal cholinergic receptor function and trophic factor (e.g., NGF) regulation (Isacson et al., 2002). In this perspective, normal physiological actions of APP, growth factors, and transmitters can be viewed as highly interactive to produce the maximal synaptic efficiency—while altered genetic, environmental, or cellular problems may slightly shift such homeostatic mechanisms toward a vicious cycle of increased Aβ accumulation, synaptic dysfunction, and finally cell degeneration (Isacson et al., TINS 2002). While I have not thought of it strictly in terms of proteases, as highlighted by Angela Biggs, the overall "growth-dynamic" hypothesis can explain how a number of factors combined with age may generate the AD pathology as a common disease in a large number of people, and by many routes. See Alzheimer's disease and Down's syndrome: roles of APP, trophic factors and ACh. Isacson et al., 2002. Download pdf file.—Ole Isacson
Novel enzyme involved in Ab vaccine action?—Posted 28 December 2000
All the researchers in AD are now astonished by the Ab vaccine. Although
extremely simple, it highlights a new way to overcome the disease. However,
I am still puzzled by the mechanism by which the vaccine works. I have the
idea that since the microglia are activated after vaccination, why does
it not phage and diminish the plaque in normal condition, and what kinds
of pathway (a new enzyme?) is involved in its action? If a new enzyme actually
expressed, can we find it using classical biochemistry or by DD-PCR to find
its cDNAand thus get its sequence? —Li Shupeng" <lishupeng76@hotmail.com>
Presenilins and transglutaminase regulation
Has anyone thought about a link between presenilins and "tissue"
transglutaminase regulation? Any research in this area ?(I havn't found any
yet!) Do researchers think this may be possible?
—Sebastien Hebert, graduate student <sehebert@hotmail.com>
Amyloidb peptide as infectious agent, analogous to prion?—Posted 19 October 2000
Karen Duff suggested I contact you about whether AlzForum is looking
into the longshot possibility that there is something infectious about bamyloid.
Karen said that there's been some talk lately about the deaths of both Henry
Wisniewski and George Glenner from amyloidosis. I know the conventional
wisdom goes strongly against any possibility of this being more than a coincidence,
but was wondering if there's any discussion of the issue.
Best, David Shenk
Comment from June Kinoshita:—Posted 20 October 2000
I believe Stanley Prusiner has made such
a suggestion.
Investigation of the role of APP during cell transformation
The mechanism by which mutant p53 gene causes cell transformation is
unclear. In order to identify genes whose expression is altered in the course
of cell transformation, the p53 overexpresser R6/#13-8 cell line and its
spontaneous transformant R6#13-8/T2 were used to differentially display
their mRNA. One clone that was down-regulated in transformed R6#13-8/T2
was identified. Sequencing analysis demonstrated that this clone was 98%
identical to rat amyloid precursor protein (APP) gene. Mutations in APP
are known to cause early-onset, autosomal dominant Alzheimer's disease.
Moreover, some findings suggest that APP may play an important role in cognitive
processes and cell death either by necrosis or by apoptosis; however, the
normal cellular function of APP remains unclear. We report here the role
of APP during cell transformation. Our research focuses on whether APP is
directly involved in cell transformation in the presence or absence of mutant
p53. A 1.1-kb fragment from the 3'end of the APP gene was obtained by reverse
transcription-polymerase chain reaction (RT-PCR). An antisense APP gene
was transduced into Rat6 embryo fibroblast cells via a retroviral vector
carrying the neomycin-resistance gene. Six clones (R6/AS-APP#4, #6, #7,
#8, #9 and #10) were obtained in neomycin-containing medium. One clone,
R6/AS-APP#8, shared similar morphology with transformed cells in normal
culture (DMEM/10% FBS). To investigate the transformability of R6/AS-APP#8
cells, a soft agar assay was performed. Expression of the APP gene in R6/AS-APP#8
is under study. Results will demonstrate the role of APP during cell transformation.
We are now transducing the antisense APP gene into R6/#13-8 cells, with
the aim of revealing the relationship between expression of APP and transformation
of R6/13-8 cells with mutant p53. —Zou Quan <zou@public1.tpt.tj.cn>
Alzheimer's and Asthma Link
Is it possible that there is a connection between the rising incidence
of asthma and Alzheimer's disease? The surfactants in the lung are the same
phospholipids that are found in the Schwann cells. It may be possible that
the body becomes immunized to specific neuronal cell membrane components.
It would be fairly simple and interesting to compare the demographics of
Alzheimer's and asthma or other chronic inflammatory diseases of the lung.—Michael Wider, PhD<mwider@flintink.com>
HSV-1 Is Frequently Found in the Brain—Posted 29 January 2004
See also the ARF Live Discussion: The Pathogen Hypothesis—Posted 30 July 2004
As you probably know, herpes simplex virus type 1 (HSV-1) infects 85-95 percent of the U.S. population,
and a similar proportion of most of the world. The virus typically
enters the body through the oral or nasal passages, and then utilizes
retrograde axonal transport mechanisms to migrate to the trigeminal
ganglia. The virus does not stop migrating at this point—it continues
following major nerves into the brain stem
(pons) using the same retrograde mechanism. Approximately 70-85 percent of
people seem to halt the penetration of the virus into the brain with
an immune response which in part involves the astrocytes[1]. This
means that the virus actually migrates into the brains of 15-30 percent of
the general population[2-8]. Pathology in the brain stem
has been noted in Alzheimer's[9,10].
HSV-1 Protein VP22 Is a MAP Similar to Tau in Functionality and
Perhaps in Shape
The HSV-1 microtubule organizing protein VP22 plays a
major role in intracellular viral assembly post-infection. This
protein is similar to tau in its functionality[11]. Consequently,
VP22 may play a role in Alzheimer's pathology, as well. An amino acid
sequence comparison of tau to VP22 reveals some homology which
may be significant in confirming involvement of HSV-1 in AD. This
homology could be especially important if labeled antibodies
to tau cross-react with VP22, confounding any attempts to identify
the separate influences of each within the brain.
Transition Metals Affect MAPs and Amyloid-β
It is widely known that transition metals such as zinc and aluminum
are associated with increasing severity of the pathology in AD. One
reason for this may be the damaging effects of these metals on
microtubule-associated proteins—MAPs[12-14]. Aluminum has been
found within tangles[15]. The damage to MAPs by metals may be one
reason that decades-old treatments which contain aluminum still remain
in use for treating herpesviruses today, since these metals could
affect VP22. These treatments include the Domeboro and Burrow's
solutions for herpes zoster[16], which contain aluminum acetate.
Another time-proven remedy for HSV-1 is Carmex, an alum-containing lip
balm. Articles on the merits of aluminum for treating herpes have been
published[17,18]. Thus, contrary to popular belief, the aluminum in
these products seems to be providing some medical benefit beyond
simply "drying out" the lesions.
While copper and zinc are noted to inactivate herpesvirus[19,20], it
is also noted that a copper/zinc chelator had a profound effect on the
disappearance of plaques in a mouse model of AD[21]. Thus, there may
be a link between the disruption of MAPs caused by transition metals
and the appearance of tangles and plaques. This link could involve
VP22, since the metals act similarly on VP22 as they do on tau.
Zinc has been noted to allow the exit of amyloid-β peptide from
within cells[22]. Recently, a significant degree of structural and
functional homology was shown between a fragment of HSV-1 glycoprotein
B and amyloid-β peptide[23]. This may point to a role for HSV-1 in
the formation of plaques and/or tangles in AD.
Free Radical Scavenging by Heavy Metals Depletes Energy Source for HSV
The negative effects of transition metals on HSV-1 may not be
limited to damaging the critical viral assembly protein VP22.
A final negative consequence of transition metals for HSV is
that they are reducing agents. The main sources of metabolic energy
for HSV-1 during latency are free radicals such as O2-, which
may be processed with an alkyl hydroperoxide-type reductase encoded
by the latency associated transcript (LAT). This metabolic pathway
is supported by observation that HSV infection induces a time-dependent
lipid peroxidation of HeLa cell plasma membranes[24], as well
as other observations about the effect of the virus on local
redox conditions[25-28]. Lastly, singlet oxygen has
been noted to completely deactivate HSV[29,30], further supporting
the case that the virus needs free radicals to thrive, since
singlet oxygen does not have an extra electron to donate to the
HSV enzyme and could act as a reducing agent by reverting to
O2-.
Thus, the elimination of free radicals by transition metals takes away
the key driver for metabolic events in HSV-1 and causes viral assembly
by VP22 to come to a halt. Without free radicals, the phosphorylation
of VP22 may cease and the protein can no longer act as an assembler
for virions[31-33]. This may explain how metals such as aluminum,
zinc, and copper deactivate herpesviruses.
Without a supply of free radicals for driving the creation of new
virions, HSV-1 would no longer be able to maintain latency in the
traditional sense of continuing to create new copies of virus.
Further, the latency-associated transcript, which includes the enzyme
that uses free radicals as a substrate, would no longer have energy to
maintain itself. The failure of the latency associated transcript may
be associated with apoptosis, since the LAT itself has been noted to
promote neuronal survival by blocking apoptosis[34-36]. Thus, the
death of an HSV-infected neuron could inadvertently
occur due to the lack of free radicals caused by the presence
of transition metals. If the neuron dies, then it could release
many copies of partially assembled virions into the intracellular
space. These unassembled particles could then form plaques,
perhaps by combining with some human proteins.
Mechanism of Action of Indomethacin in AD Consistent with HSV Biology
A small, brief clinical trial demonstrated a positive effect
of indomethacin, an NSAID, in halting the cognitive decline of
AD[37]. This drug has also been shown to block the reactivation
of latent HSV-1[38]. Other studies have reached similar conclusions
[39,40]. If HSV were a causal agent of cognitive decline, then
the activity of indomethacin in inhibiting the generation of
free radicals by blocking prostaglandin synthesis would also
serve to diminish the main metabolic source for HSV, limiting
its spread through the brain.
The Immune Conundrum: Complement-Amyloid-β Complex Affected by
Metal Ions Which May Be Derived from HSV Proteins
Amyloid-β binds
C1q, which in turn facilitates phagocytosis by microglia[41]. The C1q
binding event enhances formation of the neurotoxic, fibrillar
β-pleated form of amyloid-β[41]. This point, taken in context
with reference 22 stating that amyloid-β binding to copper or zinc
produces an ordered, membrane-penetrating structure, may imply that
C1q effects its change on amyloid-β by removing copper or zinc and
allowing it to bind to C1q. This could be very problematic for the
healthy functioning of the neuroimmune system, as C1q is inhibited by
transition metal ions[42]. Thus, while C1q binds to β amyloid as
it should, if the complex were to contain an HSV protein-transition
metal complex, such as a zinc finger protein or VP22-zinc/aluminum/copper, then the entire combination could exist in a state of immunological stasis, with microglial cells unable to properly ingest the complex
of proteins due to an inactivated C1q. Consequently, any plaques
which form from metal-containing proteins might persist in the
intracellular space for long periods, as they do in Alzheimer's
disease. —Eli Kammerman (elikam@comcast.net)
A. Wolozin B,
Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with
3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000 Oct;57(10):1439-1443. Abstract
B. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000 Nov 11;356(9242):1627-1631. Abstract
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Physiological Processes Gone Awry
Ontogenesis, Breast Milk Childhood Intelligence and AD—Posted 18 May 2001
I would appeciate feedback on the possibility that early brain development
or aberrant development/synaptogenesis/myelination may predispose to the
development of AD in the adult. This notion came to mind after perusing the
literature and contemplating the important role several AD-linked genes play
in neuron development and synaptic plasticity (ie APP, synuclein,
presenilin).
On a separate unrelated query investigating the benefits of breast feeding,
I came across several articles supporting a link between breast feeding and
childhood intelligence. A curious association given that higher educational
attainment has been reported as being protective in AD. Recently, Whalley et
al demonstrated a link between lower childhood intelligence and late-onset
dementia. Braak and Rosenberg have pointed out in several papers that the
chronological/spatial development of NFT pathology in AD reflects the
reverse pattern of myelination in the developing brain (retrogenesis).
Could there be a possible link between breast milk, brain development,
childhood intelligence and AD? Breast milk is particularly rich in
long-chain polyunsaturated fatty acids, which are essential for brain growth
and myelination. Could poor early CNS myelination related to neonatal diet
be that link? Has the possibility that breast-fed children might be
protected from the development of AD been looked at more closely, and is
anyone aware of a database in which a study of this type could be performed?
Perhaps neonatal information such as OFC, formula/breast milk nutrition and
early childhood intelligence levels would be available in the Nun population
records? —Mark Fishel (mafishel@u.washington.edu)
Comment by June Kinoshita (junekino@alzforum.org) —Posted 18 May 2001
I've also wondered about the effects of FAD mutations on
early brain development. In mice, these mutations result in apparently
"normal" brains, but I wonder if anyone has done the really painstaking
analysis of cell and synapse counts, microstructural anomalies, etc.?
Re: breastfeeding and childhood intelligence, I don't know if these
studies have controlled for socioeconomic and education factors, as well
as for changes in cultural attitudes towards breastfeeding over the past
century. In our society, I suspect that rates of breastfeeding (in
recent times) have been signficantly higher among more educated mothers,
who are better informed about the benefits of breastfeeding, and are
also more likely to have the economic means to take an extended maternal
leave and therefore be able to breastfeed (returning to a job usually
means the end of breastfeeding). In the middle of the 20th century, it
may have been that wealthier women were more likely to bottlefeed,
although one presumes that poorer women were more likely to hold jobs
and would therefore have welcomed bottlefeeding. This kind of stuff
cries out for hard data. There must be some around...
Secretory Vesicle Defect and AD? —Posted 6 April 2001
I am a student in Korea. I am happy to meet this site, and hope others
will give me advice on future research directions for AD. I think
impaired scretetory vesicle release of neurotransmitter induces
neurodegeneration and AD. I am interested in the idea of proteins that
are involved in secretory vesicle release of neurotransmitter
interacting with other proteins that play a role in AD (or in APP
processing). If anyone has insights to offer on my idea, please give me
your opinion. Thank you!! —Mi Kyung Hwang anise@hanwha.co.kr
Glycation Theory of Aging—Submitted 21 July 1997
"Another prominent theory relating fuel utilization to damage and
aging holds that toxic effects of glucose may mediate aging processes.
Glucose and other reducing sugars undergo nonenzymatic glycation reactions
with proteins and nucleic acids to generate glycoadducts termed advanced
glycosylation end-products (AGEs). It has been proposed that AGEs cause
aging by cross-linking or otherwise modifying biologic molecules involved
in critical physiologic processes. The glycation theory of aging is especially
provocative because recent studies demonstrating prevention of AGE formation
by aminoguanidine suggest potential interventions to retard aging processes."
From Stein Internal Medicine 4th Ed. [1994] on STAT! Ref CD
ROM Summer 1997
A search of Harrison's for "glycation"r eveals the following
documents in relation to glycation, but a very significant point that is
easily overlooked is the role of fructose; key player in the pathophysiology
of glycation may well be fructose; note especially the sentence from Harrison
in the text below, reproduced here :- " The rate of glycation with
fructose is seven or eight times faster than with glucose"; what damage
could be expected in the long term with a high fructose diet in susceptible
individuals; whilst the paragraghs from Harrison relate to diabetes, are
the
What causes the complications of diabetes?
The cause of diabetic complications is not known and may be multifactorial.
Major emphasis has been placed on the polyol pathway, wherein glucose is
reduced to sorbitol by the enzyme aldol reductase. Sorbitol, which appears
to function as a tissue toxin, has been implicated in the pathogenesis
of retinopathy, neuropathy, cataracts, nephropathy, and aortic disease.
The mechanism is perhaps best worked out in experimental diabetic neuropathy,
where sorbitol accumulation is associated with a decrease in myoinositol
content, abnormal phosphoinositide metabolism, and a decrease in Na+, K+-ATPase
activity. In experimental models, primacy of the polyol pathway in initiating
neuropathy was proven by showing that inhibition of aldol reductase prevented
the fall in tissue myoinositol content and the decrease in ATPase activity.
Myoinositol deficiency was not found in sural nerve biopsies from humans
with diabetic neuropathy, in contrast to animals. Aldol reductase inhibition
also has been shown to prevent experimental cataracts and retinopathy.
It thus seems possible that neuropathy and retinopathy are primarily due
to activation of the polyol pathway. It also may play a role in diabetic
nephropathy.
A second mechanism of potential pathogenetic importance is glycation
of proteins. (Current terminology uses glycation for nonenzymatic addition
of hexoses to proteins and glycosylation for enzymatic addition.) The effect
of such glycation on hemoglobin has been mentioned, but multiple proteins
in the body are altered in the same way, often with disturbed function.
Examples include plasma albumin, lens protein, fibrin, collagen, lipoproteins,
and the glycoprotein recognition system of hepatic endothelial cells. Particularly
intriguing is the effect of glycation on lipoproteins. Glycated LDL is
not recognized by the normal LDL receptor, and its plasma half-life is
increased. Conversely, glycated HDL turns over more rapidly than native
HDL. It also has been reported that glycated collagen traps LDL at rates
two to three times greater than normal collagen.
Glycated collagen is less soluble and more resistant to degradation
by collagenase than native collagen. However, it is not clear that this
is related either to the basement membrane thickening or to the tight,
waxy skin syndrome with limited joint mobility (scleroderma-like) seen
in some patients with insulin-dependent diabetes (see "Miscellaneous
Abnormalities," below). Although it is attractive to presume that
nonenzymatic glycation of protein plays a role in some degenerative complications,
the evidence is less direct than with the polyol pathway. Linkage between
the polyol pathway and the glycation sequence occurs as a result of the
glycation of collagen and other proteins by fructose generated from sorbitol.
The rate of glycation with fructose is seven or eight times faster than
with glucose.
Glycated proteins also form advanced glycation end products (AGE) through
a series of biochemical reactions that are poorly understood. Receptors
for AGE are present on macrophages and endothelial cells. Binding of AGE
to the receptors may induce the release of cytokines, endothelin-1, and
tissue factor. The latter plays a preeminent role in the initiation of
coagulation. Experimentally, AGE formation may be impaired or prevented
by aminoguanidine, an agent currently in clinical trials in humans. In
animals, it has a beneficial effect in prevention of retinopathy, nephropathy,
and neuropathy (commonly called microvascular complications), but it is
projected to have its major effect in atherosclerotic complications (commonly
called macrovascular complications).
Increased blood flow has been postulated to play an initiating role
in diabetic complications, possibly by increasing filtration of macromolecules
that function as tissue toxins. There is supportive evidence for a role
of hyperperfusion in diabetic nephropathy, but the hemodynamic hypothesis
does not appear as attractive as the first two.
Monitoring control of diabetes
( HbA1c = glycated Hb Ed.)
For those patients who measure blood glucose frequently for adjustment
of insulin dosage, an estimate of mean ambient glucose concentrations is
readily available. For other patients, and as a check on accuracy of the
self measurements, most diabetologists measure hemoglobin A1c to assess
long-term control. Hemoglobin A1c, a fast-moving minor hemoglobin component,
is present in normal persons but increases in the presence of hyperglycemia.
Its enhanced electrophoretic mobility is due to nonenzymatic glycation
of the amino acids valine and lysine.
Glucose in the aldehyde (linear) configuration condenses with a free
amino group to form a Schiff base (aldimine or pre-A1c). The Schiff base
undergoes a rearrangement to form hemoglobin A1c, a ketoamine. Aldimine
formation is reversible so that pre-A1c is labile, while ketoamine formation
is irreversible and thus stable. Pre-A1c levels change rapidly with alterations
in glucose concentrations and do not reflect long-term control, although
they are measured in chromatographic methods for determining hemoglobin
A1c. Pre-A1c must thus be removed to assess true Hb A1c values accurately.
Many laboratories employ high-performance liquid chromatography to make
the measurement. A colorimetric method utilizing thiobarbituric acid also
does not measure the labile pre-A1c fraction. When properly assayed, the
percent of glycated hemoglobin gives an estimate of diabetic control for
the preceding 3-month period. Normal values must be obtained for each lab;
on average, nondiabetic subjects have Hb A1c values of less than 6 percent,
while levels in poorly controlled patients may reach 10 to 12 percent.
Measurement of glycated hemoglobin gives an objective assessment of metabolic
control. Discrepancies between reported plasma glucose values and hemoglobin
A1c concentrations suggest either that measurement or reporting of the
former is not accurate. Measurement of glycated albumin, because of its
short half-life, can be used to monitor diabetic control over a 1- to 2-week
period but clinically is rarely used.
Circulatory abnormalities
Atherosclerosis occurs more extensively and earlier than in the general
population. The cause for this accelerated atherosclerosis is not known,
although, as discussed below, nonenzymatic glycation of lipoproteins may
be important. The atherosclerotic lesion appears to be initiated by oxidized
low-density lipoproteins (LDL) (not native LDL) in a complicated cascade
that operates through the acetyl-LDL or scavenger receptor. Both high-density
lipoproteins (HDL) and antioxidants have the capacity to impair LDL oxidation,
thereby exerting an antiatherogenic action. In experimental animals, diabetes
accelerates the oxidative process. Although lipoproteins are often in the
normal range, HDL levels tend to be low, while LDL levels are high normal
or high. A high LDL/HDL ratio favors atherogenesis, and with lower HDL
levels reverse cholesterol transport (from established lesions) would be
impaired. Lipoprotein (a) levels are elevated in IDDM but not NIDDM.
Other factors of potential importance are increased platelet adhesiveness,
possibly due to enhanced thromboxane A2 synthesis, and decreased prostacyclin
synthesis. Hyperglycemia has been reported to increase secretion of endothelin-1
in vitro, and production of nitric oxide is diminished in aortas of diabetic
rats and the coronary microvasculature of humans. These findings have not
been confirmed in human diabetes. Endothelin is a powerful vasoconstrictor
and is mitogenic for vascular smooth muscle, while nitric oxide is a vasodilator,
is antimitogenic in vascular smooth muscle, and inhibits platelet aggregation.
Advanced glycation end products may be important, as discussed below
Atherosclerotic lesions produce symptoms in a variety of sites. Peripheral
deposits may cause intermittent claudication, gangrene, and, in men, organic
impotence on a vascular basis. Surgical repair of large-vessel lesions
may be unsuccessful because of the simultaneous presence of widespread
disease of the small vessels. Coronary artery disease and stroke are common.
Silent myocardial infarction is thought to occur with increased frequency
in diabetes and should be suspected whenever symptoms of left ventricular
failure appear suddenly. Diabetes also may be associated with the clinical
picture of cardiomyopathy, in which heart failure occurs in the face of
angiographically normal coronary arteries and the absence of other identifiable
causes of heart disease. As in nondiabetic subjects, smoking is a major
risk factor for both coronary and peripheral vascular disease and should
be avoided. Hypertension is also a significant risk factor in many diabetic
patients.
Can diabetic complications be prevented by meticulous control of
diabetes?
As mentioned earlier, the strongest evidence that the answer is yes
comes from the Diabetes Control and Complications Trial (DCCT). Additional
clinical evidence supports the view that metabolic environment per se influences
or causes complications independent of genetic factors. For example, kidneys
from donors who have neither diabetes nor a family history of diabetes
develop characteristic lesions of diabetic nephropathy within 3 to 5 years
after transplantation into a diabetic recipient. Diabetic nephropathy did
not develop when a kidney was transplanted into a diabetic subject whose
disease had been reversed by pancreatic transplantation prior to renal
transplantation. It also has been reported that kidneys manifesting diabetic
nephropathy demonstrated reversal of the lesion when transplanted into
normal recipients. All these findings suggest that hyperglycemia or some
other aspect of the abnormal metabolism of diabetes causes or influences
the development of complications. On the other hand, additional factors,
probably genetic, must normally play a role. This follows from the fact
that diabetic subjects with decades of poor control may escape the ravages
of the late complications and from the fact that typical diabetic complications
may be found in patients at the time of diagnosis of diabetes or even in
the absence of hyperglycemia.
Meticulous control with insulin infusion pumps has been reported to
decrease microalbuminuria, improve motor nerve conduction velocity, lower
plasma lipoproteins, and decrease capillary leakage of fluorescein in the
retina. Width of the capillary basement membrane in skeletal muscle also
has been decreased. The changes are small in general, however, and of questionable
biologic significance. Thus firm evidence does not exist to show that late
complications can be reversed by long-term near-normalization of the plasma
glucose level. Progression of retinopathy has been reported despite successful
reversal of diabetes by pancreatic transplantation. The progression of
diabetic complications after return of the plasma glucose level to normal
or near normal has been termed hyperglycemic memory.
Some investigators suggest that the mechanism is formation of advanced
glycation end products during hyperglycemia which, being irreversible,
continue their effects long term
As discussed earlier, the question of intensive therapy for all patients
with diabetes remains open at the time of this writing pending evidence
that the results achieved in DCCT can be matched in the general population.
Care of persons with diabetes is often delivered by nonspecialists who
do not have available teams of support personnel, as was the case in the
DCCT. There seems little question, however, that the thrust of treatment
will be toward tighter control.
From "Harrison's Principles of Internal Medicine, 13/e Copyright 1994
McGraw-Hill, Inc. I would like to acknowledge the use of information from
both Harrison & STAT! Ref on CD ROM. Further information on availability
of these CDs are available from:- http://www.tetondata.com
—Allen Gale <
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