Brain Research 886 2000 54–66 www.elsevier.com locate bres
Interactive report
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Alzheimer’s disease: a dysfunction of the amyloid precursor protein
Rachael L. Neve , Donna L. McPhie, Yuzhi Chen
Department of Psychiatry , Harvard Medical School, MRC 223 McLean Hospital, 115 Mill St., Belmont, MA 02478, USA
Accepted 25 August 2000
Abstract
In this review, we argue that at least one insult that causes Alzheimer’s disease AD is disruption of the normal function of the amyloid precursor protein APP. Familial Alzheimer’s disease FAD mutations in APP cause a disease phenotype that is identical with
the exception that they cause an earlier onset of the disease to that of ‘sporadic’ AD. This suggests that there are molecular pathways common to FAD and sporadic AD. In addition, all individuals with Down syndrome, who carry an extra copy of chromosome 21 and
overexpress APP several-fold in the brain, develop the pathology of AD if they live past the age of 40. These data support the primacy of APP in the disease. Although APP is the source of the b-amyloid Ab that is deposited in amyloid plaques in AD brain, the primacy of
APP in AD may not lie in the production of Ab from this molecule. We suggest instead that APP normally functions in the brain as a cell surface signaling molecule, and that a disruption of this normal function of APP is at least one cause of the neurodegeneration and
consequent dementia in AD. We hypothesize in addition that disruption of the normal signaling function of APP causes cell cycle abnormalities in the neuron, and that these abnormalities constitute one mechanism of neuronal death in AD. Data supporting these
hypotheses have come from investigations of the molecular consequences of neuronal expression of FAD mutants of APP or overexpression of wild type APP, as well as from identification of binding proteins for the carboxyl-terminus C-terminus of APP.
2000 Elsevier Science B.V. All rights reserved.
Theme : Disorders of the nervous system
Topic : Degenerative disease: Alzheimer’s – beta amyloid
Keywords : Alzheimer’s disease; Amyloid precursor protein; Neuronal death
1. Introduction possession of an extra copy of chromosome 21 Down
syndrome; or it can be caused by mutations in the amyloid 1.1. APP, Ab, and Alzheimer disease
precursor protein APP gene on chromosome 21 or by mutations in the presenilin genes on chromsome 1 and 14.
All individuals with Alzheimer disease AD experience Additional genetic complexicity is conferred on it by the
a progressive loss of cognitive function, resulting from a fact that the e4 allele of the APOE gene is a major risk
neurodegenerative process characterized classically by the factor for the development of AD. Thus, it is not likely that
deposition of b-amyloid Ab in plaques and in the AD is caused by a single molecular event.
cerebrovasculature, and the formation of neurofibrillary Numerous mechanisms for the neuronal cell death in
tangles in neurons. Additional pathological hallmarks of AD have been proposed. One of these is the amyloid
AD include granulovacular degeneration, loss of synapses hypothesis, which suggests that deposition of Ab is a
and decreases in cell density in distinct regions of the primary event in the pathological cascade for AD. This
brain. Alzheimer disease does not have a simple etiology. argument is based on in vitro studies showing that Ab is
It can occur as a ‘sporadic’ event; it can result from the toxic to neurons and on the measurement of increased
release of Ab by cells carrying familial AD FAD mutant genes. There are two major carboxyl-terminal variants of
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Published on the World Wide Web on 11 September 2000.
Ab. Ab is the major species secreted from cultured
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Corresponding author. Tel.: 11-617-855-2413; fax: 11-617-855-
cells and found in cerebrospinal fluid, while Ab is the
3793.
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E-mail address : nevehelix.mgh.harvard.edu R.L. Neve.
major component of amyloid deposits reviewed in Ref.
0006-8993 00 – see front matter
2000 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 2 8 6 9 - 9
R .L. Neve et al. Brain Research 886 2000 54 –66
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[118]. Cells expressing FAD mutants of APP and the transmission [28]. There has been some question of
presenilins are reported to secrete increased amounts of whether C100 exerts its neurotoxic effects from the inside
Ab , suggesting a link of this variant of Ab to AD
or the outside of the cell [23,117]. Our data of the past 6
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pathogenesis. Consequently, a leading hypothesis for the years suggest strongly that C100 kills from inside the cell;
etiology of AD is that increased Ab is a shared
this is supported by the observation that C100 is not
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molecular correlate of FAD mutations, and that it repre- secreted, even when it carries a signal peptide [19,14,66].
sents a gain of deleterious function that can cause FAD Although at least one group has reported neurotoxicity due
[38] and may be an essential early event in AD [118]. to the addition of C100 to the culture medium [50], we
While this ‘amyloid hypothesis’ is attractive, molecular believe that that type of neurotoxicity is mechanistically
mechanisms other than those mediated by extracellular Ab different from the neurodegeneration that we observe upon
could also lead to AD neurodegeneration. expression of C100 within primary neurons.
These mechanisms are likely to be linked in some way The findings that APP interacts with the signaling
to the b-amyloid protein precursor APP, the source of molecule G , that FAD mutants of APP can cause G -
o o
Ab. One of the most compelling pieces of evidence that mediated apoptosis in neuronal cells, and that these same
links AD neurodegeneration to APP and or its Ab-con- FAD mutants of APP cause the intracellular accumulation
taining derivatives is the early finding that the APP gene is of C100, suggested to us the following working hypoth-
on chromosome 21: virtually all individuals trisomic for esis: In the brain a portion of APP is present as an integral
this chromosome show AD-like neuropathology by the age plasma membrane protein that mediates the transduction of
of 40. Additionally, it has been discovered that specific extracellular signals into the cell via its C-terminal tail, and
mutations in APP cause some forms of familial FAD. abnormal accumulation of its Ab-containing C-terminal
These data have raised the possibility that AD may result tail in the neuron causes progressive dysfunction of APP
from an alteration in the normal function of APP [74,76], signaling in AD, resulting in apoptosis. This hypothesis has
and have refocused attention on the delineation of the been supported by the finding that the intracellular C-
function that APP subserves in the brain. It has been terminal tail of APP interacts with the cell cycle protein
shown [47,83] that in the brain a percentage of APP is APP-BP1 [10,9], and with members of the Fe65 family of
present on the cell surface, and it is proposed [76,83] that adaptor proteins reviewed in Ref. [89]. Additional sup-
this cell surface APP mediates the transduction of extracel- port for this hypothesis emerged with the recent report [60]
lular signals into the cell via its C-terminal tail. that the C31 peptide of APP, which is derived from C100
Nishimoto and his colleagues [75] showed that APP and within which are contained the binding sites for the
binds to the brain-specific signal transducing G protein G ; above proteins, is elevated in AD brain and is a potent
o
independent confirmation of this finding has subsequently inducer of apoptosis.
been published [4,5]. It was then discovered [113] that V642 ‘London’ FAD mutants of APP induce neuronal
DNA fragmentation, a feature of apoptosis, in a neuronal
2. Processing of APP
