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
||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...
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...
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...
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