In this paper, Wang et al. report on how they were able to manufacture, with short incubation times, prions capable of infecting wild-type mice. This is an important finding. Looking at the prion field, and the body of research produced over the years, the major efforts were focused on using recombinant proteins to produce infective prions. In our 2004 paper (Legname et al., 2004), we demonstrated that it was possible to create low levels of infectivity using only recombinant prion protein produced in Escherichia coli. After that, there was a major push in research to find out how to enhance these low levels. The main advance came from Surachai Supattapone, formerly of Stanley Prusiner’s lab, when he employed RNA molecules to enhance the production of PrPSc in vitro. Around the same time, Claudio Soto’s group perfected protein misfolding cyclic amplification (PMCA), another important contribution. From then on it was clear that cofactors were probably needed to enhance PrP conversion, and that is basically what the group of...  Read more

In this paper, Wang et al. report on how they were able to manufacture, with short incubation times, prions capable of infecting wild-type mice. This is an important finding. Looking at the prion field, and the body of research produced over the years, the major efforts were focused on using recombinant proteins to produce infective prions. In our 2004 paper (Legname et al., 2004), we demonstrated that it was possible to create low levels of infectivity using only recombinant prion protein produced in Escherichia coli. After that, there was a major push in research to find out how to enhance these low levels. The main advance came from Surachai Supattapone, formerly of Stanley Prusiner’s lab, when he employed RNA molecules to enhance the production of PrPSc in vitro. Around the same time, Claudio Soto’s group perfected protein misfolding cyclic amplification (PMCA), another important contribution. From then on it was clear that cofactors were probably needed to enhance PrP conversion, and that is basically what the group of Jiyan Ma has just described in their Science paper. They used lipids and RNA, combined with PMCA, to produce highly infectious samples.

This is an important piece of work because it once again confirms that PrP is definitely necessary to create prions, and, perhaps most importantly, it shows that it is actually possible to induce high infectivity with the addition of other cofactors, which are still not well defined but nevertheless necessary to increase the infectivity in the samples. As a matter of fact, these prions are very similar to the mouse-adapted scrapie prions that we already know about, such as the Rocky Mountain Laboratory (RML) strain and others. But the neuropathology that they show is clearly different from RML and any other mouse-adapted prions. All these wild-type prions in mice rarely lead to widespread vacuolation, but the authors here do see vacuolation in many different areas of the brain. A contamination with RML would not explain this.

One puzzling piece of information that is presented in the work of Ma and coworkers is the delayed incubation time upon second passage of these novel prions to the same wild-type recipient mice. Usually, subsequent passages lead to abbreviated incubation times.

In addition, it would be interesting to receive additional information about the stability of their novel prion strain, and more biochemical characterization beyond proteinase K (PK) digestion. One of the things we did with our synthetic prions was to show that they were a completely new set of prions, because they possessed higher stability in terms of resistance to chemical or chaotropic agent denaturation. We found that with synthetic prions, in addition to the neuropathology and to all the other major indications that this is a different prion, the biochemical stability is completely different from any wild-type prion. The authors here did not provide stability data, unfortunately, because it would have given additional indication that they are actually handling something completely different. In our recent work, we also showed how incubation times vary based on the conformation and stability of different synthetic prions (Legname et al., 2006; Colby et al., 2009).

One suggestion of Ma and coworkers’ paper is that whenever you have PK resistance, you have prions, but that’s not always true, because some prions are sensitive to PK attack (Colby et al., 2010).

View all comments by Giuseppe Legname

The generation of a pathogenic molecule through protein misfolding cycling amplification (PMCA) in the presence of phospholipid is reminiscent of the "globulomer" complex formed from Aβ and specific lipids (Barghorn et al., 2005). There may also be some relationship to the role of gangliosides in creation of a toxic Aβ moiety (Kakio et al., 2002; Yamamoto et al., 2007). Perhaps lipid-protein interactions play a general and critical role in the development of peptide misfolding disorders.

References:
Barghorn S, Nimmrich V, Striebinger A, Krantz C, Keller P, Janson B, Bahr M, Schmidt M, Bitner RS, Harlan J, Barlow E, Ebert U, Hillen H. 2005. Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer's disease. J Neurochem. 95:834-847. Abstract

Kakio A, Nishimoto S, Yanagisawa K, Kozutsumi Y, Matsuzaki K., 2002, Interactions of amyloid beta-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. Biochemistry 41:7385-7390. Abstract

Yamamoto N, Matsubara E, Maeda S, Minagawa H, Takashima A, Maruyama W, Michikawa M, Yanagisawa K., 2007, A ganglioside-induced toxic soluble Abeta assembly. Its enhanced formation from Abeta bearing the Arctic mutation. J. Biol. Chem. 282:2646-2655. Abstract

View all comments by Steve Barger

The studies by Meyer-Luehman et al. extend insights into the in vivo formation of amyloid deposits by amyloid "seeds" that may be hetero- and/or homo-amyloidogenic inducers of amyloid fibrillization. This is significant because these types of studies will lead to the clarification of the perplexing conundrum of why there is a frequent co-occurrence of multiple different types of amyloids in neurodegenerative disorders characterized by brain amyloidosis. Indeed, double and triple neurodegenerative brain amyloidoses appear to far exceed in incidence and prevalence any neurodegenerative brain amyloidosis linked to a single amyloidogenic protein or peptide, and this enigma demands clarification if we are to develop more effective therapies for these disorders.

For example, with respect to Aβ deposits, these may occur by themselves as pathological signatures of single brain amyloidoses, such as cerebral amyloid angiopathy (CAA), which most commonly manifests clinically as stroke. This notwithstanding, CAA is more commonly an incidental finding in neurologically normal...  Read more

The studies by Meyer-Luehman et al. extend insights into the in vivo formation of amyloid deposits by amyloid "seeds" that may be hetero- and/or homo-amyloidogenic inducers of amyloid fibrillization. This is significant because these types of studies will lead to the clarification of the perplexing conundrum of why there is a frequent co-occurrence of multiple different types of amyloids in neurodegenerative disorders characterized by brain amyloidosis. Indeed, double and triple neurodegenerative brain amyloidoses appear to far exceed in incidence and prevalence any neurodegenerative brain amyloidosis linked to a single amyloidogenic protein or peptide, and this enigma demands clarification if we are to develop more effective therapies for these disorders.

For example, with respect to Aβ deposits, these may occur by themselves as pathological signatures of single brain amyloidoses, such as cerebral amyloid angiopathy (CAA), which most commonly manifests clinically as stroke. This notwithstanding, CAA is more commonly an incidental finding in neurologically normal individuals, suggesting that Aβ deposits may not be sufficient in and of themselves to cause a neurodegenerative dementing disease. In contrast, neurodegenerative dementia linked to Aβ amyloidosis is commonly a double or triple brain amyloidosis with coexistent tau amyloid (in the form of neurofibrillary tangles, or NFTs), and this dementia is, of course, known as Alzheimer disease (AD).

However, most familial and sporadic cases of AD are actually triple brain amyloidoses since α-synuclein amyloid also is deposited in Lewy bodies (LBs) together with NFTs and senile plaques, and this disorder is known as the LB variant of AD (LBVAD). Notably, LBVAD is the most common subtype of AD. Recent studies from the Lee/Trojanowski group have begun to dissect out mechanisms whereby α-synuclein and tau can cross-seed the fibrillization of each other to form amyloid fibrils, and further research on this may help clarify the common co-occurrence of LBs and tangles in the same patient (1).

Additionally, further studies are needed to understand how tau and Aβ might cross-fibrillize or promote the fibrillization of each other. Much earlier studies by our group demonstrated potential avenues to explore these issues further—using model systems that antedated the development of transgenic mouse models of brain amyloidoses—by injecting purified PHFtau into rat brains, which induced deposits of Aβ associated with the PHFtau injection sites (2,3). However, transgenic mouse models of brain amyloidoses resulting from the overexpression or regulatable expression of mutant or wild-type tau and α-synuclein or the Aβ precursor protein are much more powerful model systems in which to explore these questions further. This is demonstrated very elegantly in the studies by Meyer-Luehman et al. Further dissection of the cross-seeding by hetero- and/or homo-amyloidogenic inducers of amyloid fibrillization could extend these elegant studies by immunodepletion of AD and LBVAD extracts to remove not only Aβ, but also tau amyloid and α-synuclein amyloid to understand the differential contributions of each of these three amyloidogenic proteins in the induction of Aβ.

References:
1. Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 2003 Apr 25;300(5619):636-40. Abstract

2. Shin RW, Bramblett GT, Lee VM, Trojanowski JQ. Alzheimer disease A68 proteins injected into rat brain induce codeposits of beta-amyloid, ubiquitin, and alpha 1-antichymotrypsin. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6825-8. Abstract

3. Shin RW, Lee VM, Trojanowski JQ. Aluminum modifies the properties of Alzheimer's disease PHF tau proteins in vivo and in vitro. J Neurosci. 1994 Nov;14(11 Pt 2):7221-33. Abstract

View all comments by John Trojanowski

BACE1 is the principal β-secretase for generation of amyloid-β peptides. Since the identification of BACE1, several lines of BACE1 knockout mice have been made, which are viable and show no major behavioral and pathological abnormalities, suggesting that BACE1 is a safe therapeutic target for Alzheimer disease (AD). Notably, some BACE1 KO mice show premature lethality and subtle alterations in emotional response and locomotor activities. BACE1 KO neurons also display subtle changes in synaptic plasticity and sodium conductance. These deficits are not noted in all the reported mice, but similar discrepancies in behavioral phenotyping have been noticed in mice derived from different strain backgrounds and gene targeting vectors.

Willem and colleagues are the first to show a convincing neuropathological abnormality in BACE1 KO mice. An observation that the highest expression of BACE1 protein correlates with the onset of peripheral nerve myelination promotes them to examine the progression of myelination in the sciatic nerve of BACE1 KO mice. They find that axons of...  Read more

BACE1 is the principal β-secretase for generation of amyloid-β peptides. Since the identification of BACE1, several lines of BACE1 knockout mice have been made, which are viable and show no major behavioral and pathological abnormalities, suggesting that BACE1 is a safe therapeutic target for Alzheimer disease (AD). Notably, some BACE1 KO mice show premature lethality and subtle alterations in emotional response and locomotor activities. BACE1 KO neurons also display subtle changes in synaptic plasticity and sodium conductance. These deficits are not noted in all the reported mice, but similar discrepancies in behavioral phenotyping have been noticed in mice derived from different strain backgrounds and gene targeting vectors.

Willem and colleagues are the first to show a convincing neuropathological abnormality in BACE1 KO mice. An observation that the highest expression of BACE1 protein correlates with the onset of peripheral nerve myelination promotes them to examine the progression of myelination in the sciatic nerve of BACE1 KO mice. They find that axons of BACE1 KO mice are hypomyelinated from early postnatal stages to adulthood. Interestingly, mice deficient in cell-cell signaling protein type III neuregulin 1 (NRG1-β3) and its receptor, ErbB, display a very similar hypomyelination in peripheral axons, indicating a cross-talk between BACE1 and the NRG1-β3/ErbB signaling pathway. In line with this notion, membrane-bound NRG1 full-length protein accumulated in BACE1 KO mice and exogenous expression of BACE1 increased the release of the NRG1 ectodomain in culture, suggesting that NRG1-β is a novel substrate for BACE1. The cleavage by BACE1, or in combination with TACE, may result in the release of the EGF-like domain of NRG-β from neurons. This domain interacts with the receptor tyrosine kinase ErbB at the surface of Schwann cells, promoting the myelination process. It appears that BACE1 cleaves NRG1-β at the stalk region, but the precise cleavage site has not been revealed.

There are two major questions to be addressed in the future research. The first question is whether the lack of BACE1-mediated cleavage of NRG-β is solely responsible for the hypomyelination in BACE1 KO mice. Willem and colleagues’ findings do not completely rule out the involvement of other BACE1 substrates. For example, it will be interesting to examine whether the myelination is altered in APP KO mice, which display decreased locomotor activity and forelimb grip strength. The second question is whether BACE1 is involved in other functions of NRG1 family signaling molecules. NRG1 plays many essential roles in the CNS, heart and other peripheral tissues. It is important to revisit BACE1 KO mice to examine potential pathology in these systems.

In summary, Willem and colleagues reveal a novel function of BACE1 in myelination. The findings raise some concern about the safety of inhibiting BACE1 as a treatment for AD. Nevertheless, the generally healthy BACE1 KO mice still make BACE1 the best therapeutic target for the inhibition of Aβ production in AD.

View all comments by Huaibin Cai

It’s a Wrap; Axonal Myelination Is Regulated by the Alzheimer Disease Target, BACE
A fundamental developmental process has once again crossed paths with a major player in the pathogenesis of Alzheimer disease. Shortly after its discovery, BACE, via its interaction with neuregulin-1, has been implicated in the molecular neurobiology of central and peripheral axon myelination. Data from several labs have shown that specific members of the neuregulin-1 (NRG1) family of trophic factors are critical to Schwann cell differentiation, proliferation, survival, and now to the process of myelination itself. Whether axons are myelinated singly (and the number of myelin wraps required) or left unmyelinated and ensheathed in bundles, is governed by expression of the type III isoform of neuregulin-1 (Michailov et al., 2004; Taveggia et al., 2005; Chen et al., 2006; Ogata et al., 2004): It is the...  Read more

It’s a Wrap; Axonal Myelination Is Regulated by the Alzheimer Disease Target, BACE
A fundamental developmental process has once again crossed paths with a major player in the pathogenesis of Alzheimer disease. Shortly after its discovery, BACE, via its interaction with neuregulin-1, has been implicated in the molecular neurobiology of central and peripheral axon myelination. Data from several labs have shown that specific members of the neuregulin-1 (NRG1) family of trophic factors are critical to Schwann cell differentiation, proliferation, survival, and now to the process of myelination itself. Whether axons are myelinated singly (and the number of myelin wraps required) or left unmyelinated and ensheathed in bundles, is governed by expression of the type III isoform of neuregulin-1 (Michailov et al., 2004; Taveggia et al., 2005; Chen et al., 2006; Ogata et al., 2004): It is the expression level of NRG1 that communicates axon caliber to the Schwann cell.

Neuregulin-1 isoforms are ligands for heterodimeric combinations of ErbB receptor tyrosine kinases, specifically ErbB2, B3 and B4 (the EGF receptor is known as ErbB1). After binding to their cognate receptors, these ligands induce tyrosine phosphorylation and subsequent downstream activation of the PI3K (phosphatidyl inositol-3 kinase) pathway (Maurel and Salzer, 2000). The importance of neuregulin-1 cannot be overemphasized: pan-NRG1 as well as ErbB2, ErbB3, and ErbB4 KO mice are each embryonic lethals, and neuregulin-1 gene products in the CNS have been implicated in numerous other processes including neurotransmitter receptor regulation (see review by Falls, 2003).

Akt is the signaling node downstream of neuregulin and PI3K that is most implicated in survival and the specialization of Schwann cells and oligodendrocytes to form myelin (Flores et al., 2000; Li et al., 2001; Taveggia et al., 2005). Akt is already familiar to those studying neurodegeneration, motor neuron disease, and schizophrenia (Emamian et al., 2004; Humbert et al., 2002; Kaspar et al., 2003; Magrane et al., 2004). In Schwann cells, Akt transduces the neuregulin signal to inactivate the proapoptotic proteins Bad (Li et al., 2001) and GSK3β (Ogata et al., 2004), as well as to increase the expression of proteins that specify myelin differentiation: MAG (Ogata et al., 2004); P0; PMP22; and MBP (Chen et al., 2006). The transcription factors, Oct-6 and Krox-20 fill in the signal cascade (Taveggia et al., 2005).

What’s new in two recent papers is that type III neuregulin-1 has become the newest substrate of BACE-1, indicating this enzyme has an essential role to play in the decision to myelinate axons, and by how much. The studies by Hu et al. (2006) and Willem et al. (2006) have implicated BACE-1, the β-secretase enzyme for the amyloid precursor protein, as being a critical regulator of the levels of cleaved type III neuregulin-1. Hu et al. decided to examine myelination in BACE-1 deficient mice because BACE is transported into axons, along with APP, by a kinesin-1-dependent pathway. Willem et al. on the other hand noted that BACE-1 expression is highest in the developmental period corresponding to peripheral myelination. Both papers show that in the absence of BACE-1, myelination is reduced to the same degree as is seen in neuregulin hypomorphs (having only one copy of the NRG1 gene) or in conditional knockdowns of ErbB2. Measurement of the g-ratio (interior/exterior fiber diameter) shows a significant reduction in the number of myelin wraps associated with both central and peripheral axons when the BACE-1 gene has been inactivated. In the Hu et al. study, the decrease in myelination paralleled a reduction in expression of compact myelin proteins such as myelin basic protein (MBP) and the proteolipid protein (PLP). Willem et al. show through the added generation of BACE-1/2 compound mutants and BACE-2 mutant mice that BACE-1 activity alone is responsible for the hypomyelination phenotype. It is interesting that BACE-deficient mice also show abnormal bundling of small-diameter, unmyelinated axons (Willem et al.), in agreement with Taveggia et al., who use co-cultures of NRG1-/- neurites with Schwann cells to prove that NRG1 signaling is required for this critical function, too. Thus, normal ensheathment is not a default in the absence of NRG1 or BACE.

In both studies, the absence of BACE-1 leads to the accumulation of the inactive, full-length type III neuregulin-1 precursor and a corresponding decrease in the cleavage product or active ligand in brain. Presumably, BACE-1 cleaves the transmembrane precursor to release the soluble extracellular domain from the axons. Willem et al. produced a fusion between type III neuregulin-1 and secreted alkaline phosphatase to show that co-transfection with BACE-1 led to a direct increase in cleavage and release of the extracellular fragment. A likely direct interaction between BACE-1 and NRG1 was concluded. The ligand is then free to interact with and activate ErbB receptor tyrosine kinases on adjacent myelinating cells. How this diffusion takes place is presently unclear.

As expected from the loss of NRG1 cleavage in BACE-1-null mice, signaling in the PI3K/Akt pathway is reduced as revealed by the reduction in activated pAkt levels and drops in MBP and PLP in brain (Hu et al.). To prove that BACE-1-/- neurons cannot activate PI3K/Akt signaling in Schwann cells in a functional way might require some added work. This could be addressed, for instance, by showing that an axotomized nerve graft from a normal mouse can rescue myelination of a recovering host BACE-null axon (i.e., after transplantation into the transected defect of a peripheral nerve belonging to a recipient BACE-1-/- mouse) if prior gene transfer with myrAkt is attempted.

It should be emphasized that both authors found heterozygote BACE-1 mice to be phenotypically normal. Moreover, BACE-1 levels drop considerably in the adult state. These alone might suggest that partial inhibition of BACE-1, as advocated for AD therapy, would have no chance for adverse effects. Unfortunately, such mice still produce substantial amounts of β amyloid (Cai et al., 2001; Luo et al., 2001) and do not correct cognitive defects when crossed with APP/PS-1 transgenic AD mice (Laird et al., 2005). Thus, it will still be important to know the full impact of BACE-1 inhibition in the adult animal. A conditional KO model may be one approach to this question. However, there already exist cautionary signs. For instance, it is already known that BACE-1-deficient mice have a number of undesirable effects relating to impaired spatial reference memory and synaptic function (LTD-reversal) (Laird et al., 2005) as well as reduced pain threshold (Hu et al., 2006). BACE inhibition also has the theoretical effect of mitigating the protective back-signaling role of the NRG1-intracellular domain (Bao et al., 2003). Neuregulins may also have beneficial effects on APP metabolism and protection from Aβ (Rosen et al., 2003; Di Segni et al., 2005) that could be susceptible to BACE inhibition. Theoretically, remyelination could be impaired after certain central and peripheral injuries in BACE-1-inhibited patients. Ironically, loss of Notch signaling from inhibition of γ-secretase activity has somewhat dampened the enthusiasm of that approach to reduce Aβ production (Haass, 2004). With every “wrap” there seems to appear an interesting twist, which solves yet another puzzle but never the most important one—how do we treat Alzheimer disease?

View all comments by Henry Querfurth
View all comments by Kenneth Rosen

This is a very interesting work. It has been shown that the most common misdiagnosis of Creutzfeldt-Jakob disease (CJD) is Alzheimer disease (1). The symptoms and pathology of both diseases overlap (2). There can be spongy changes in Alzheimer disease patients while senile plaques are also found in CJD patients (2). The causes of the two diseases might overlap as well: epidemiological evidence suggests that people eating meat more than four times a week for a prolonged period have a three times higher chance of suffering a dementia than long-time vegetarians (3), although such a conclusion remains to be verified. A previous study also showed that the brains of the young people who died from the new CJD variant in Britain even look like Alzheimer brains (4). All this evidence indicates there could be some interaction between CJD and Alzheimer disease; however, no study has yet shown a direct link between these two diseases.

In the current issue of PNAS, Edward Parkin et al. report that the wild-type prion protein, whose mutant form is the culprit in CJD, prevents β-site...  Read more

This is a very interesting work. It has been shown that the most common misdiagnosis of Creutzfeldt-Jakob disease (CJD) is Alzheimer disease (1). The symptoms and pathology of both diseases overlap (2). There can be spongy changes in Alzheimer disease patients while senile plaques are also found in CJD patients (2). The causes of the two diseases might overlap as well: epidemiological evidence suggests that people eating meat more than four times a week for a prolonged period have a three times higher chance of suffering a dementia than long-time vegetarians (3), although such a conclusion remains to be verified. A previous study also showed that the brains of the young people who died from the new CJD variant in Britain even look like Alzheimer brains (4). All this evidence indicates there could be some interaction between CJD and Alzheimer disease; however, no study has yet shown a direct link between these two diseases.

In the current issue of PNAS, Edward Parkin et al. report that the wild-type prion protein, whose mutant form is the culprit in CJD, prevents β-site APP secretase (BACE1) from accessing its substrate APP, which leads to a decrease in Aβ production (5). In other words, PrPc inhibits the β-secretase cleavage of APP with no effect on either BACE1 level or enzymatic activity. Further, the authors provide evidence that the polybasic N-terminus of PrPc and its localization to lipid rafts are required for the inhibition of β-secretase, suggesting that such regulation might depend on the localization of prion protein to the cholesterol-rich lipid rafts and be mediated by the interaction between the N-terminal polybasic region of prion protein and glycosaminoglycans (5). The actual mechanism, though yet to be confirmed, suggests that prion protein might have a normal cellular function as a lipid raft modulator. The study also reveals a potential link between CJD and Alzheimer disease: the mutant prion, which is involved in CJD, fails to have a similar effect as its wild-type counterpart does, indicating loss of function of endogenous prion protein could unleash BACE1 to access APP and therefore increase Aβ production. If this is true, it explains why CJD and Alzheimer disease are so alike.

References:
1. Harrison PJ, Roberts GW. "Life, Jim, but not as we know it"? Transmissible dementias and the prion protein. Br J Psychiatry. 1991 Apr;158:457-70. Review. Abstract

2. Brown P. Central nervous system amyloidoses: a comparison of Alzheimer's disease and Creutzfeldt-Jakob disease. Neurology. 1989 Aug;39(8):1103-5. No abstract available. Abstract

3. Giem P, Beeson WL, Fraser GE. The incidence of dementia and intake of animal products: preliminary findings from the Adventist Health Study. Neuroepidemiology. 1993;12(1):28-36. Abstract

4. Liberski PP. Amyloid plaques in transmissible spongiform encephalopathies (prion diseases). Folia Neuropathol. 2004;42 Suppl B:109-19. Review. Abstract

5. Parkin ET, Watt NT, Hussain I, Eckman EA, Eckman CB, Manson JC, Baybutt HN, Turner AJ, Hooper NM. Cellular prion protein regulates {beta}-secretase cleavage of the Alzheimer's amyloid precursor protein. Proc Natl Acad Sci U S A. 2007 Jun 15; [Epub ahead of print] Abstract

View all comments by Yong Shen

The paper by Parkin et al. is of extreme interest to the community. Since the physiological function of both proteins APP and PrP is still under intense discussion, the data presented in the paper show nicely this interaction.

As known from the glial cell line-derived neurotrophic factor (GDNF) and its GPI-anchored dimeric receptor (GFRa1), which transduces the information intracellularly via RET, there are also parallels for PrP and APP. Does PrP function as a GPI-anchored receptor which transduces the information by influencing APP cleavage or multimerization? What is the factor binding to PrP primarily?

View all comments by Jens Pahnke

Lauren et al. report that Aβ oligomers bind to PrPc and that the detrimental effect of Aβ on hippocampal LTP is not observed in PrPc knockout mice; PrPc presumably mediates this detrimental effect not by direct modulation of glutamate receptors but in an indirect way. There are earlier studies hinting at an association of Aβ with PrPc (e.g., Brown, 2000; Schwarze-Eicker et al., 2005) but the demonstration of a specific Aβ-binding site on PrPc opens up possibilities of exploring the role of PrPc in Alzheimer disease and the role of Aβ in prion diseases; since a high-affinity PrPc binding site for Aβ should not be accidental, it might also indicate a physiological role for Aβ. With picomolar concentrations of Aβ monomers and oligomers stimulating synaptic activity (Puzzo et al., 2008), certain species of Aβ oligomers should not be toxic under physiological conditions and their binding to PrPc may contribute to normal synaptic activity.

It has been proposed that some effects of PrPc involve an interaction of PrPc with a surface...  Read more

Lauren et al. report that Aβ oligomers bind to PrPc and that the detrimental effect of Aβ on hippocampal LTP is not observed in PrPc knockout mice; PrPc presumably mediates this detrimental effect not by direct modulation of glutamate receptors but in an indirect way. There are earlier studies hinting at an association of Aβ with PrPc (e.g., Brown, 2000; Schwarze-Eicker et al., 2005) but the demonstration of a specific Aβ-binding site on PrPc opens up possibilities of exploring the role of PrPc in Alzheimer disease and the role of Aβ in prion diseases; since a high-affinity PrPc binding site for Aβ should not be accidental, it might also indicate a physiological role for Aβ. With picomolar concentrations of Aβ monomers and oligomers stimulating synaptic activity (Puzzo et al., 2008), certain species of Aβ oligomers should not be toxic under physiological conditions and their binding to PrPc may contribute to normal synaptic activity.

It has been proposed that some effects of PrPc involve an interaction of PrPc with a surface receptor and that the binding site of PrPc for this receptor overlaps segment 105-125 of PrPc (review Westergard et al., 2007). In their discussion, Lauren et al. suppose that "a putative PrPc-associated transmembrane co-receptor is likely to have a central role in Alzheimer’s disease-mediated neurodegeneration." As several publications indicate that the neurotrophin receptor p75 is essential for Alzheimer-like degeneration (e.g., review Capsoni and Cattaneo, 2006; Sotthibundhu et al., 2008), it is a candidate for such a co-receptor.

In this context, the demonstrated binding site of Aβ oligomers on PrPc (around 95-110) might support the Aβ-crosslinker-hypothesis (see Current Hypotheses), which suggests an Aβ-binding site within PrPc segment 91-123 and describes possible physiological and pathological effects of an Aβ-mediated interaction between the neurotrophin receptor p75 and PrPc, APP, and α-synuclein; the recently found Aβ-binding site within the stalk and transmembrane domain of p75 (see my recent hypothesis) would be crucial to such interactions and link Aβ-related diseases. Aggregate species of Aβ can activate p75, and available or newly formed short Aβ oligomers may crosslink p75 and PrPc. The cooperation of stimulated p75 and PrPc would activate sphingomyelinase and NADPH oxidase in a synergistic feed-forward process, and p75-Aβ-PrPc complexes could provide reactive oxygen species and elevated intracellular calcium required for components of p75 signaling. A "rapid inhibitory effect of p75(NTR) on NMDA-R currents that antagonizes TrkB-mediated NMDA-R potentiation" (Sandoval et al., 2007) should be increased by excess p75-activating Aβ and might be negatively influenced by a lack of PrPc. Excess Aβ might also induce oxidative stress and/or disturb cellular calcium homeostasis through disproportionate PrPc-receptor (and perhaps also PrPc-PrPc) crosslinking.

References:
Brown, D.R. (2000) PrPSc-like prion protein peptide inhibits the function of cellular prion protein. Biochem J 352, 511-8. Abstract

Capsoni, S. and Cattaneo, A. (2006) On the Molecular Basis Linking Nerve Growth Factor (NGF) to Alzheimer’s Disease. Cell Mol Neurobiol 26, 619-33. Abstract

Puzzo D, Privitera L, Leznik E, Fà M, Staniszewski A, Palmeri A and Arancio O. (2008) Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci. 28(53), 14537-45. Abstract

Sandoval, M., Sandoval, R., Thomas, U., Spilker, C., Smalla, K.H., Falcon, R., Marengo, J.J., Calderon, R., Saavedra, V., Heumann, R., Bronfman, F., Garner, C.C., Gundelfinger, E.D. and Wyneken, U. (2007) Antagonistic effects of TrkB and p75(NTR) on NMDA receptor currents in post-synaptic densities transplanted into Xenopus oocytes. J Neurochem 101, 1672-84. Abstract

Schwarze-Eicker, K., Keyvani, K., Gortz, N., Westaway, D., Sachser, N. and Paulus, W. (2005) Prion protein (PrPc) promotes beta-amyloid plaque formation. Neurobiol Aging 26, 1177-82. Abstract

Sotthibundhu, A., Sykes, A.M., Fox, B., Underwood, C.K., Thangnipon, W. and Coulson, E.J. (2008) Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor. J Neurosci 28, 3941-6. Abstract

Westergard, L., Christensen, H.M. and Harris, D.A. (2007) The cellular prion protein (PrP(C)): its physiological function and role in disease. Biochim Biophys Acta 1772, 629-44. Abstract

View all comments by Rudolf Bloechl

This is outstanding work that makes a strong link for alterations in PrPc for synaptic and neuronal dysfunction. Several investigators have shown that PrPc participates in cellular signaling (see review by Linden et al., 2008); it is likely that some of these pathways may be altered/disturbed or overactivated by Aβ oligomers.

References:
Linden R et al. Physiology of the prion protein. Physiol Rev. 2008 Apr;88(2):673-728. Abstract

View all comments by Marco Prado