Live Discussion: Intracellular Aβ in Alzheimer's Disease
Gunnar Gouras led this live discussion on 16 May 2000. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
View Transcript of Live Discussion — Posted 31 August 2006View Comments By:
Samuel Gandy — Posted 15 May 2000
Dominic Walsh, Dennis Selkoe — Posted 15 May 2000
Gunnar K. Gouras — Posted 16 May 2000
By Gunnar Gouras
Recently, an increasing number of reports are suggesting
that intracellular accumulation of Aβ42 may play
an important pathological role in AD. It is now established
that the Aβ42 form of ß-amyloid increases
with all known familial AD mutations and that the first
amyloid plaques are composed of Aβ42, and not
the more abundantly secreted Aβ40. Cell biological
studies are increasingly emphasizing the subcellular
site of Aβ production, and are finding that Aβ42
is abundant intracellularly as compared with secreted,
especially in neurons. Remarkably, it was reported from
the laboratory of Virginia Lee that an insoluble pool
of intracellular Aβ42 increases dramatically within
neuronal NT2 cells as a function of aging in culture
et al., 1998). Recently, Aβ42 accumulation
was reported both in neurons in the vicinity of plaques
A et al.) and in neurons of AD susceptible brain
regions even prior to plaques or tangle pathology (Gouras
GK et al., Am J Pathol 2000). The recent publication
J et al in JAMA showing increases in brain Aβ
with early cognitive dysfunction and even prior to plaques
and tangles, support the proposal that soluble Aβ
and not plaques may initiate AD pathology. Two other
recent Aβ ELISA studies are supportive of this
J et al, Exp Neurol 1999, 158:328-337; McLean
CA et al., Ann Neurol 1999, 4:860-6)
These recent publications counter the prevailing hypothesis of AD pathogenesis
(via aggregated extracellular Aβ toxicity within plaques) and raise
the question of whether neuronal Aβ42 accumulation may play a direct
role in causing neuronal dysfunction, neuronal death and dementia. The prevailing
hypothesis based on the the landmark discovery from the laboratory of Bruce
Yankner that Aβ when added to neurons is neurotoxic, may therefore
have to be modified. A central question now is whether intraneuronal Aβ42
accumulation merely reflects increased production with resultant increased
extracellular neurotoxicity or whether intraneuronal Aβ42 can also
directly damage neurons from within.
Arguments Potentially Supporting Intracellular Mechanism
- Marked increase of intracellular Aβ42 with aging in culture of
neuronal NT2 cells (Skovronsky
- Presence of intraneuronal Aβ42 in AD brain (Mochizuki
A et al, 2000) and in AD vulnerable neurons even before plaque and
tangle pathology (Gouras et al,
- Supraphysiological levels of Aβ needed to cause extracellular
Aβ toxicity in experimental models
- mRNAs isolated from plaques are derived from neurons (Ginsberg
et al. 1999).
The following could argue against Aβ plaque toxicity (i.e. aggregated,
Congophilic plaque) and support an intracellular scenario, but also an extracellular
toxic mechanism via soluble prefibrillar or protofibrillar Aβ.
- Behavioral and physiological changes in AD transgenics even prior to
plaques (see references in Gouras et al., Am J Pathol)
- Inflammatory changes prior to plaques (Sheng
et al J. Neurochem, 2000)
- Recent ELISA data implicating soluble Aβ with AD disease progression (see Naslund
J et al )
- Evidence in vitro of suppression of LTP and apoptosis in neurons
treated with low-molecular weight derivatives of Aβ and protofibrillar
Aβ (see Live Discussion)
Arguments Against Intracellular Mechanism
- Extracellular Aβ cause neurotoxicity in vitro and in
- Transgenic mice develop plaques without obvious neuronal loss, which
argues against a necessary role for Aβ accumulation in cell bodies
in plaque pathology.
- A recent transgenic model with a neuronal promoter for ßAPP causing
extracellular Aβ deposition in vasculature and brain parenchyma (Calhoun
ME, et al, 1999)
- Studies have shown that neurons can internalize Aβ; therefore
intracellular Aβ (and associated toxicity) may be derived from extracellular
BA, et al, 1998)
1) Recent ELISA studies indicate that Aβ increases do correlate
with cognitive status and also indicate that Aβ increases prior to
plaque and tangle pathology. One study suggested that it is soluble Aβ
that especially correlates well with dementia. So the question is where
is this Aβ? A recent study suggests that the earliest Aβ42 accumulation
occurs within neurons. Given that evidence increasingly indicates that the
especially important Aβ42 can accumulate within neurons, should we
not be focusing more on this pool of Aβ?
2) A recent study on the Novartis transgenic mice indicates prominent
vascular Aβ40 deposition when ßAPP is driven by a neuronal promoter.
Does this prove that extracellular Aβ is key? But then why is vascular
Aβ less commonly Aβ42 and AD appears linked more closely with
3) Although we still do not have a good understanding on the normal role
of ßAPP or even Aβ, neurons clearly generate intracellular Aβ
under normal conditions. The laboratory of Konrad Beyreuther has proposed
that Aβ is important for normal transport of ßAPP along processes.
May an alteration in a normal intraneuronal function of Aβ play a
role in AD?
4) Evidence increasingly indicates that not only secreted but also intracellular
Aβ increases with familial AD mutations. What may influence increases
in intracellular Aβ in most forms of AD?
1) Determine whether plaques can form within neurons at nerve terminals
via intraneuronal accumulation.
2) Create cell and preferably animal models that can isolate the potential
pathological role of intracellular versus extracellular Aβ.
3) Will experimental therapies aimed at reducing plaque load cause cognitive
improvements, and if not, could this be from continued intraneuronal toxicity?
4) If intracellular Aβ accumulation precedes tau pathology, determine
the intracellular events that lead to subsequent cell pathology.
5) Work out the physiological mechanisms that can drive the acceleration
of intracellular Aβ accumulation.
6) Determine where within neurons Aβ42 accumulation preferentially
Live discussion held 16 May 2000.
Participants: Bruce Yankner, Huaxi Xu, Austin Yang, Gasparini, Charles
Glabe, Virginia Lee, Steve Younkin, Dean Hartley, Dominic Walsh, Janet Walsh,
Gunnar Gouras, June Kinoshita
Note: Transcript has been edited for clarity and accuracy.
Charles Glabe: Hi! Hey Austin!
Austin: Hi boss.
Charles Glabe: Boss?
Austin: Oh…I guess I don't work for you anymore.
Austin: Hi Virginia.
June: Hi Virginia, can you chat?
Virginia Lee: I am trying to figure out how to chat.
June: Hi Steve!
Steve Younkin: Hello everyone
Bruce: Hi Austin.
Charles Glabe: So what's all this talk about intracellular amyloid?
What is it?
Virginia Lee: Charlie, you said that intracellular amyloid is
garbage but does the garbage do anything?
June: Garbage can be a fertilizer.
Charles Glabe: Yes, Virginia, even garbage can be bad!
Virginia Lee: Charlie, how bad can intracellular amyloid be?
Charles Glabe: Don't know; but the range is probably from dysfunction
to cell death.
Virginia Lee: Steve and Bruce, do you agree with Charlie?
Bruce: Virginia - Depends on whether it's picked up and how you
Charles Glabe: Bruce, Whaddaya mean by "picked up";
Do cells cruise for amyloid?
Virginia Lee: Bruce, which is worst for the cell: The amyloid
that the cell picks up or the amyloid produced by the cells?
Bruce: I mean disposed. Is lysosomal or endosomal Aβ inert
Charles Glabe: It is both
Bruce: Perhaps - but we need data.
June: Let's bring this meeting to order. I'll throw out a question:
Is there a consensus that there exist intracellular accumulations of Aβ?
Gunnar, can you respond?
Gunnar Gouras: I certainly think that intraneuronal Aß42
Charles Glabe: Yes, but Aβ is only a fraction of what is actually
accumulating. There is also a lot of insoluble misfolded APP and fragments
of APP and I think that this confuses people who would expect that what
accumulates extracellularly would be the same as what is accumulating inside.
Bruce: Charlie - do you think these APP metabolites accumulate
in extracellular amyloid?
Charles Glabe: Probably for a while until they get proteolytically
removed. There are some reports of APP immunoreactivity in extracellular
Steve Younkin: Charlie, are you referring to intraneuronal accumulations
in the AD brain?
Charles Glabe: Yes, but most of the mechanistic data comes from
culture models: cells and tissue slices.
Charles Glabe: Steve, are there two of you here?
Steve Younkin: Yes I'm here despite frequent reports to the contrary.
Virginia Lee: Charlie, do you think the extracellular accumulation
of APP metabolites comes from dead cells?
Charles Glabe: Don't know. I see two possibilities: Dead cells
or chronically-infected ones. I favor the latter.
Virginia Lee: Charlie, what do you mean by chronically infected
Charles Glabe: They are the ones that have the intracellular amyloid
that accumulates ad infinitum (apparently). What do Steve and Bruce think?
Bruce: There is certainly evidence for dead neurons within plaques
which could serve as the source. But the idea that intracellular aggregates
can also be actively secreted is an attractive hypothesis.
Charles Glabe: But dead neurons don't synthesize anything and
the amyloid deposits are much larger than the cells.
Dominic Walsh: Perhaps the species secreted by cells are small
but provide the nidus for plaque formation?
Charles Glabe: A more likely penultimate source for the amyloid:
Bruce: I think that most of the extracellular deposition must
come from extracellular Aβ, but the intracellular aggregates from dead
neurons may serve as seeds.
Virginia Lee: I agree with Bruce.
Gunnar Gouras: So do I.
Charles Glabe: Could be, but what accumulates is not like what
is secreted; it is mostly 42.
Bruce: I think it is important to distinguish what is secreted
from what aggregates. The small Aβ42 component is disproportionately
Charles Glabe: The biochemical kinetics of Aβ assembly do
not predict spontaneous amyloid growth at nanomolar concentrations. Even
for Aβ 42
Dominic Walsh: Yeah, but test tube studies with synthetic peptide
may be very far removed from what goes on in vivo
Charles Glabe: Sure, but it begs the question of what.
Bruce: This is a key point - how does the process get started?
Peter Lansbury's seeding hypothesis addresses this question, but does not
tell us what gives rise to the seeds.
Charles Glabe: I certainly think that extracellular growth can
go on, but it doesn't explain all the cellular pathology like the dense
granules in dystrophic neurites that are packed with APP and Aβ immunoreactivity.
Steve Younkin: I think Charlie makes a good point. That so many
AD brains have Aß42 exclusively deposited is hard to reconcile with
simple extracellular deposition -- or with simple extracellular growth of
cellularly generated seeds.
Charles Glabe: Exactly Steve.
Charles Glabe: Only CVA [cerebrovascular amyloid] deposits look
like they are diffusion based.
huaxi: I agree with both Steve and Charles
June: What form of Aβ are the dense granules composed of?
Charles Glabe: Dense granules are a little mysterious, but by
IR, they seem to contain misfolded, insoluble APP and Aβ.
Bruce: Peter Lansbury's seeding hypothesis suggests that small
extracellular insoluble seeds could catalyze the process but this doesn't
tell us about the origin of the seeds. Certainly in vitro Aβ42 aggregates
more readily. I don't think this argues for an intracellular or extracellular
Bruce: Virginia, do your NT2 cells that accumulate intracellular
Aβ42 secrete insoluble Aβ?
Charles Glabe: Actually, when you have mixtures of 40 and 42,
they co-assemble with the same intermediate kinetics over a broad range
of 40/42 ratios. Although 42 aggregates a little faster, one of the differences
that gets overlooked is potentially significant for cells: Aβ 42 is
much more resistant to degradation than 40; particularly in the endosomal/lysosomal
Bruce: What do you think is the basis for that - is it aggregation
state? And is that difference observed at physiological concentrations of
Dominic Walsh: Is the rate of degradation really greater for 42
than 40 or is it merely that 42 forms more readily forms degradation resistant
Charles Glabe: It could be the aggregation state, but simple in
vitro proteinase K digestion shows that 42 is intrinsically more resistant,
independent of whether it is soluble or in fibrils. The stuff that is resistant
to degradation and accumulating inside cells is definitely aggregated and
Steve Younkin: What is the "killer experiment" to determine
whether intracellular Aß is important in AD. Is there one?
Charles Glabe: Human APP knockout? You said "Killer".
June: The role of intracellular Aβ being discussed seems to
be as seeding material for extracellular aggregation. Does anyone think
it can be toxic intracellularly?
Gouras: I think it needs to be considered as a possibility.
Bruce: I think a first step is to determine if it does anything
to cells. Virginia - do your NT2 cells that accumulate intracellular 42
show increased neuronal death or degeneration? How about even chronically
dysfunctional - is there any evidence?
Charles Glabe: Sure, in amyloid expressing cells the cells will
just fill up with it.
Gunnar Gouras: I think it needs to be considered as a possibility.
Steve Younkin: June, it could be, but is it?
Charles Glabe: It doesn't have to be acutely toxic to be a problem.
June: Is there evidence of cells "filling up" with Aβ?
Charles Glabe: In vitro, it is easy to demonstrate cultured cells
filling up with Aβ.
Gunnar Gouras: In regards to June's question a few responses ago,
I do think that there is evidence for vulnerable neurons "filling up
with Aβ" - see my background/discussion.
huaxi: If someone can link intracellular Aβ to tau phosphorylation
and apoptosis-that would be the killer.
Charles Glabe: By the way, did you see the report by the Mandelkows
in PNAS that tau is just another amyloid?
June: No, what is the Mandelkow's argument?
Charles Glabe: Tau neurofibrillary tangles have a cross beta core,
just like other amyloids.
June: Is this [intracellular Aβ hypothesis] a question of
choking to death on garbage, or does the garbage trigger a specific pathogenic
Charles Glabe: I favor the idea that it triggers some pathologic
cell response that is common for all types of accumulating garbage, like
June: What are those pathologic responses to amyloids?
Charles Glabe: O2 radicals,
Bruce: There is increasing evidence for activation of a variety
of signal transduction cascades that mediate cell death by caspase activation.
This theme has also appeared for polyglutamine repeat containing proteins.
Charles Glabe: Attempts to clear the insoluble garbage: send it
to Siberia (the neurite).
June: And then what?
Charles Glabe: If clearance can't keep up with accumulation, the
neuron loses (functionally and maybe literally).
June: Gunnar, do you agree with either of these scenarios, or
do you think other factors are involved?
Gunnar Gouras: I would agree that accumulating intraneuronal Aß42
most likely is not a good thing. I believe that various mechanisms may
be involved first in promoting intraneuronal Aß accumulation, and
subsequently in causing neuronal dysfunction and cell death potentially
also via tau, oxidative stress and/or apoptotic mechanisms.
June: How do amyloids result in oxidative stress?
Charles Glabe: I don't know how amyloids induce oxidative stress,
but they all seem to.
Virginia Lee: One major problem in studying oxidative stress using
antibodies in postmortem tissue is that you don't know whether the amyloid
aggregates get modified by oxidative stress because it is sitting inside
the cells for a long time or that oxidative stress is the cause of cells
Charles Glabe: That is why we have cell culture models.
Bruce: Virginia - do you know whether your NT2 cells that accumulate
intraneuronal 42 show increased oxidative stress?
Virginia Lee: Bruce, we have not done those experiments yet. But
I think they are worth doing.
Virginia Lee: I think all intracellular aggregates kill cells.
For example, NFTs, and Lewy bodies, although they are comprised of different
proteins, i.e. tau and alpha synuclein respectively, they form beta-pleated
sheet structures intracellularly and they kill cells. Therefore, I favor
a similar mechanism for intracellular amyloid doing the same.
Charles Glabe: Me too. I like common themes.
Charles Glabe faints and falls over
June: Quick, throw some water on Charlie!
Bruce: I think it's more complicated than that. There is good
evidence that in Huntington's disease the intraneuronal inclusions may in
fact be protective not neurotoxic (Sandou et al., 1999; Klement et al.,
1999). There may be toxic and non-toxic forms.
Charles Glabe: I don't buy it. Protective schmotective.
Bruce: Is Charlie still unconscious?
huaxi: In all other neurodegenerative cases, inclusions are in
the cytoplasm. Aβ seems to be generated and accumulated in the secretory
Austin: Charlie and Virginia: Astrocytes and microglia can certainly
accumulate much more aggregates than neurons and they are very resistant
Virginia Lee: Austin, you may be right for amyloid. However, tau
inclusions and synuclein inclusions in glial cells (e.g., oligodendrocytes
and astrocytes cause them to die.
Bruce: Virginia - the MTT assay would be an easy pilot.
Virginia Lee: Yes.
Charles Glabe: The consequences are different for neurons, astros
and micros. Astros and Micros can just die and then they will be replaced.
Neurons cannot be replaced and they have serious work to do. That is why
all these disease are primarily neurodegenerative.
June: Virginia, do the NT2 cells secrete the Aβ accumulations?
Virginia Lee: June, the NT2N cells secrete both Aβ40 and 42,
but they accumulate a pool of Aβ42 in the ER that is not secreted.
Charles Glabe: Are you sure it stays in the ER? It is pretty hard
to metabolically label a pool that doesn't turn over.
Virginia Lee: Charlie, I don't know exactly where it is since
we have not had any luck localizing it. However, using the APPdeltaKK mutant
in NT2N cells, we know that the pool of Aβ42 produced by this construct
is not secreted.
Bruce: Perhaps they have to die in order to release it - analogous
to the dead neuronal profiles reported at the epicenter of plaques.
Virginia Lee: June, I do believe that this pool of Aβ 42 could
be quite toxic since they accumulate with age in culture. One of my hypothesis
is that intracellular accumulation of Aβ42 eventually kill neurons and
serve as a nidus for the secreted Aβ42 and 42 to form a classical plaque.
StephenSnyder: Gotta leave now, thanks for the insights.
Dominic Walsh: Virginia, is the accumulated Aβ that requires
formic acid extraction aggregated or simply bound to carrier proteins?
Virginia Lee: Dominic: As I said to Charlie, we have not had luck
localizing intracellular Aβ42 yet but we are still trying. If the material
is bound to other proteins, it is bound very tightly since we have not been
able to extract much of this material except with formic acid.
Dominic Walsh: I'm thinking about Alex Roher's finding that formic
acid treatment appears to release Aβ from carrier proteins.
Austin: Charlie: we have been looking at the solubility of cell
surface (extracellular), protease resistant 42. They are very soluble and
don't aggregate on SDS-PAGE
Charles Glabe: I agree; very little if any insoluble intracellular
Aβ gets secreted. There is a lot of APP that hangs out with the insoluble
intracellular Aβ, but is it bound? Probably, but data would help.
June: What are the implications of these intra vs. extracellular
issues when it comes to intervention strategies?
Charles Glabe: Secretase inhibitors may not be effective. Clearance
of extracellular deposits a la immunization may not be beneficial.
June: We're at the end of our hour. I want to invite everyone
to make a closing statement re: what next?
Gunnar Gouras: It won't be easy to provide a final answer to this
issue, but I agree that we need to study this insoluble intracellular Aβ
Charles Glabe: I'm sorry that Steve Snyder left already because
I would like to say that we need to put more effort into understanding intracellular
amyloid. Maybe we can make a living off of this for a few more years.
Virginia Lee: Bye everybody!
June: Thanks for joining us!
hartley: Thank you for the interesting discussion!
June: It appears we are all out of words for the time being. Thank
you all very much for taking part in today's discussion.
||Comments on Live Discussion
Comment by: Samuel Gandy
Submitted 15 May 2000
Posted 15 May 2000
The idea that intracellular Aβ injures neurons and causes
dementia prior to the formation of extracellular deposits
is not obviously reconcilable with other evidence indicating
that "full-blown" structural pathology precedes dementia
(Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler
M, Masdeu J, Kawas C, Aronson M, Wolfson L. Clinico-pathologic
studies in dementia: nondemented subjects with pathologically
confirmed Alzheimer’s disease. Neurology 1988; 38: 1682-1687.
; Price JL, Morris JC. Tangles and plaques in nondemented
aging and "preclinical" Alzheimer’s disease. Ann Neurol
1999; 45: 358-368. Abstract
I would like to comment on several of the points made
by Dr. Gouras in the background to our discussion. The
prevailing amyloid hypothesis of AD does not require
that plaques be the major toxic Aβ component. Rather,
extracellular aggregated Aβ is proposed to be the
major toxic component, and toxicity can be mediated
by extracellular Aβ prior to plaque formation. This
hypothesis is consistent with in vitro and in vivo Aβ
toxicity studies from many labs which show that extracellular
aggregated Aβ, not plaques per se, is neurotoxic. The
proposal that intracellular Aβ is also toxic and contributes
to the neurodegenerative process should be carefully
considered. However, there is still not a single report
that shows intracellular Aβ toxicity. Sam Gandy's
point is important - the literature suggests that dementia
occurs only when extracellular pathology is evident.
This does not rule out a contribution of intracellular
Aβ, but it suggests that such an effect would be
unlikely to precede extracellular Aβ deposition.
Several arguments were advanced to support an intracellular Aβ
1. Recent reports show intraneuronal Aβ42 in a cultured neuronal cell
line, in AD brain and in AD-vulnerable neurons before plaques and
tangles. The key issue is not whether Aβ is present in neurons but
whether it does anything when sequestered in an intracellular vesicular
compartment. Many groups have found that intracellular Aβ, including
Aβ42, is a minor component of total Aβ production. We have detected
intracellular Aβ42 in human cortical neuronal cultures from normal and
Down's syndrome specimens, but this is a minor component of total Aβ,
even in 2 month old cultures. More importantly, in AD brains,
intracellular Aβ42 appears to be a minor component of total Aβ42
2. It was noted that extracellular Aβ toxicity requires
"supraphysiological levels". The micromolar concentrations of
aggregated Aβ required for Aβ toxicity in vitro is in the range of Aβ
levels in affected AD cortex (Selkoe et al., 1986). Moreover, Aβ
toxicity in vivo requires only a single plaque-equivalent dose (Geula et
al., 1998). If Aβ toxicity occurred in the physiological nanomolar
range, we might all have AD.
3. The behavioral and physiological changes in APP-transgenic mice
prior to the appearance of many plaques argues against a plaque-based
mechanism. The behavioral studies in APP-transgenic mice have been
difficult to interpret because they are very strain-dependent. I think
it is safe to say that something is happening to the transgenic brain
which is separable from plaque formation, as suggested by Karen Hsiao
and Lennart Mucke. However, what it is and whether it is relevant to AD
is unclear. It is certainly too early to conclude anything about its
cause. My guess is that it may relate to pre-plaque accumulation of
4. The recent study by Naslund et al., which correlates brain Aβ levels
with disease progression, has been taken as evidence implicating soluble
Aβ. However, this study does not provide any information about the
physical or cellular state of Aβ. The paper suggests that Aβ levels can
be elevated prior to the appearance of plaques, but this Aβ could be
extracellular, intracellular, soluble, oligomeric or fibrillar.
My own view is that both extracellular and intracellular Aβ may
contribute to the neurodegenerative process. However, to seriously
consider a role for intracellular Aβ, we need a study that convincingly
demonstrates intracellular Aβ toxicity.
View all comments by Samuel Gandy
Comment by: Dennis Selkoe, ARF Advisor (Disclosure), Dominic Walsh, ARF Advisor
Submitted 15 May 2000
Posted 15 May 2000
From various studies examining the toxicity of Aβ,
it is clear that random coil monomeric Aβ is not
toxic whereas oligomeric aggregates (protofibrils, ADDLs
or fibrils) are. Thus the critical issue with respect
to Aβ toxicity is its aggregation state. An ideal anti-aggregation
therapy would prevent the production of the first toxic
assembly of Aβ.
It has been widely assumed that Aβ aggregation is initiated
extracellularly. However, we have demonstrated (data recently presented
at the Society for Neuroscience in Miami) that SDS-stable oligomers of
Aβ (primarily dimers) are first generated intraneuronally. This
finding represents the first direct observation of the aggregation state
of Aβ in human neurons (earlier studies on intraneuronal Aβ did
not deal with aggregation state) and establishes that oligomerization is
initiated within cells. Irrespective of whether intraneuronal oligomers
are toxic per se or mediate their effect after export to the
extracellular space, their site of origin is now known. Thus, it would
be desirable to interfere with Aβ dimerization within neurons.
View all comments by Dennis Selkoe
View all comments by Dominic Walsh
Comment by: Gunnar K. Gouras
Submitted 16 May 2000
Posted 16 May 2000
|Reply to Sam Gandy by Gunnar Gouras
We all agree that "full-blown" structural pathology
(plaques and tangles) precede and accompany dementia.
What we are especially considering is whether there
is any role for intraneuronal Aβ in causing neuronal
dysfunction early on in the AD disease process. I don't
think that anyone is convinced that intraneuronal Aβ
has a clear and seperate neurotoxic effect, but rather
some of us are intrigued by the possibility that there
may be an early pathological role for intraneuronal
Aβ42. Dementia is preceded by probably at least a few
years of initially subtle and then mild cognitive impairement
(MCI), the pathological basis of which is not established.
I appreciate the instructive comments of Dr. Yankner, and would like to
add (Re: his point 1) that a major reason for my interest in
intracellular Aβ is that I studied the same brains as Naslund et al. did
in their ELISA study with immunohistochemistry, and observed the most
prominent Aβ as intraneuronal Aβ42 within AD vulnerable neurons and not
in the brain parenchyma. I do not know whether this is from Aβ42 uptake
(see Bahr BA et l., 1998) or from endogenous accumulation. I also wonder
if he has tried to extract Aβ42 from neuron cell lysate with formic acid
(see Skovronsky et al., 1998) or another more stringent method. Lastly,
there was one report published in Nature Medicine last year of neuronal
degeneration in thepresence of intraneuronal Aβ42 acumulation but not
plaque formation in a FAD PS1 trangenic mouse strain (Chui et al.,
View all comments by Gunnar K. Gouras