Elsevier

Brain Research

Volume 886, Issues 1–2, 15 December 2000, Pages 54-66
Brain Research

Interactive report
Alzheimer’s disease: a dysfunction of the amyloid precursor protein1

https://doi.org/10.1016/S0006-8993(00)02869-9Get rights and content

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 β-amyloid (Aβ) that is deposited in amyloid plaques in AD brain, the primacy of APP in AD may not lie in the production of Aβ 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.

Introduction

All individuals with Alzheimer disease (AD) experience a progressive loss of cognitive function, resulting from a neurodegenerative process characterized classically by the deposition of β-amyloid (Aβ) in plaques and in the cerebrovasculature, and the formation of neurofibrillary tangles in neurons. Additional pathological hallmarks of AD include granulovacular degeneration, loss of synapses and decreases in cell density in distinct regions of the brain. Alzheimer disease does not have a simple etiology. It can occur as a ‘sporadic’ event; it can result from the possession of an extra copy of chromosome 21 (Down syndrome); or it can be caused by mutations in the amyloid precursor protein (APP) gene on chromosome 21 or by mutations in the presenilin genes on chromsome 1 and 14. Additional genetic complexicity is conferred on it by the fact that the ϵ4 allele of the APOE gene is a major risk factor for the development of AD. Thus, it is not likely that AD is caused by a single molecular event.

Numerous mechanisms for the neuronal cell death in AD have been proposed. One of these is the amyloid hypothesis, which suggests that deposition of Aβ is a primary event in the pathological cascade for AD. This argument is based on in vitro studies showing that Aβ is toxic to neurons and on the measurement of increased release of Aβ by cells carrying familial AD (FAD) mutant genes. There are two major carboxyl-terminal variants of Aβ. Aβ1–40 is the major species secreted from cultured cells and found in cerebrospinal fluid, while Aβ1–42 is the major component of amyloid deposits (reviewed in Ref. [118]). Cells expressing FAD mutants of APP and the presenilins are reported to secrete increased amounts of Aβ1–42, suggesting a link of this variant of Aβ to AD pathogenesis. Consequently, a leading hypothesis for the etiology of AD is that increased Aβ1–42 is a shared molecular correlate of FAD mutations, and that it represents a gain of deleterious function that can cause FAD [38] and may be an essential early event in AD [118]. While this ‘amyloid hypothesis’ is attractive, molecular mechanisms other than those mediated by extracellular Aβ could also lead to AD neurodegeneration.

These mechanisms are likely to be linked in some way to the β-amyloid protein precursor (APP), the source of Aβ. One of the most compelling pieces of evidence that links AD neurodegeneration to APP and/or its Aβ-containing derivatives is the early finding that the APP gene is on chromosome 21: virtually all individuals trisomic for this chromosome show AD-like neuropathology by the age of 40. Additionally, it has been discovered that specific mutations in APP cause some forms of familial FAD. These data have raised the possibility that AD may result from an alteration in the normal function of APP [74], [76], and have refocused attention on the delineation of the function that APP subserves in the brain. It has been shown [47], [83] that in the brain a percentage of APP is present on the cell surface, and it is proposed [76], [83] that this cell surface APP mediates the transduction of extracellular signals into the cell via its C-terminal tail.

Nishimoto and his colleagues [75] showed that APP binds to the brain-specific signal transducing G protein Go; independent confirmation of this finding has subsequently 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 cell line. This fragmentation is independent of Aβ1–42 production [114] and is mediated by the Gβ2γ2 complex of Go[29]. These data support the notion that APP has an intrinsic signaling function in the neuron, which becomes ligand-independent when APP is mutated at V642.

To examine the mechanism by which FAD APP might cause apoptosis in neurons, we [66] expressed five different Alzheimer mutations of APP in primary neurons via recombinant herpes simplex virus (HSV) vectors, and quantified the levels of APP metabolites. The predominant intracellular accumulation product was a C-terminal fragment of APP that co-migrated with the protein product of an HSV recombinant expressing the C-terminal 100 amino acids (C100) of APP. Interestingly, we had proposed previously that C100 is involved in the etiology of Alzheimer disease [73]. It is neurotoxic in vitro [116], [24], [97], [101], [57] and is amyloidogenic [17], [18], [19], [64], [111], [27], [105]. In addition, expression of C100 in vivo can cause neuropathology that is similar in some ways to that in AD, including neurodegeneration and cognitive dysfunction [3], [25], [48], [71], [72], [80], [91], [104], as well as increases in acetylcholinesterase [92] and abnormalities in synaptic transmission [28]. There has been some question of whether C100 exerts its neurotoxic effects from the inside or the outside of the cell [23], [117]. Our data of the past 6 years suggest strongly that C100 kills from inside the cell; this is supported by the observation that C100 is not secreted, even when it carries a signal peptide [19], [14], [66]. Although at least one group has reported neurotoxicity due to the addition of C100 to the culture medium [50], we believe that that type of neurotoxicity is mechanistically different from the neurodegeneration that we observe upon expression of C100 within primary neurons.

The findings that APP interacts with the signaling molecule Go, that FAD mutants of APP can cause Go-mediated apoptosis in neuronal cells, and that these same FAD mutants of APP cause the intracellular accumulation of C100, suggested to us the following working hypothesis: In the brain a portion of APP is present as an integral plasma membrane protein that mediates the transduction of extracellular signals into the cell via its C-terminal tail, and abnormal accumulation of its Aβ-containing C-terminal tail in the neuron causes progressive dysfunction of APP signaling in AD, resulting in apoptosis. This hypothesis has been supported by the finding that the intracellular C-terminal tail of APP interacts with the cell cycle protein APP-BP1 [10], [9], and with members of the Fe65 family of adaptor proteins (reviewed in Ref. [89]). Additional support for this hypothesis emerged with the recent report [60] that the C31 peptide of APP, which is derived from C100 and within which are contained the binding sites for the above proteins, is elevated in AD brain and is a potent inducer of apoptosis.

Section snippets

Processing of APP

Most of what we know about APP processing has come from work with cultured cells. APP matures through the constitutive secretory pathway. Some fraction of the APP is endoproteolytically cleaved at the cell surface within the Aβ sequence by the α-secretase, which generates the neuroprotective secreted amyloid precursor protein (APP) and nonamyloidogenic 3 kDa Aβ secreted products [81], [37], [65]. APP is readily detected in human plasma and cerebrospinal fluid.

Endocytosis of cell surface APP

APP as a signaling molecule

The possibility that APP may act as a signaling receptor was first proposed on the basis of its predicted amino acid sequence, which suggested that APP was a type 1 intrinsic membrane protein consistent with the structure of a ‘cell surface receptor.’ [49]. However, subsequent studies of the function of APP concentrated largely on the secreted ectodomain, because of a lack of direct evidence that mature APP exists on the cell surface with intact intracellular, transmembrane, and intracellular

Apoptosis in Alzheimer disease

The notion that a form of cell suicide called apoptosis participates in the neuropathology of AD was raised by Su et al. [100], when they reported evidence for DNA fragmentation in neurons in AD brain. Although other groups have also detected this feature of apoptosis in AD brain, many in the field have been skeptical of the idea that the neurons that die in AD undergo apoptosis, partly because DNA fragmentation can also be caused by oxidative damage [106] or by postmortem autolysis [98].

Cell cycle abnormalities in Alzheimer’s disease

The implication of apoptosis in AD etiology is consistent with the numerous findings of cell cycle abnormalities in AD. Apoptosis and the cell cycle are closely tied together, and the reexpression of cell cycle markers has been linked with the occurrence of certain types of neuronal cell death [40], [39], [22]. One interpretation of these findings [56] is that a neuron is committed to the permanent cessation of cell division, so if for any reason it is forced to reenter the cell cycle after

Conclusions

We propose that mechanisms other than accumulation of Aβ may be the cause of AD neurodegeneration and cognitive impairment. In particular, we suggest that the disease may be a consequence of disruption of function of APP. Convincing data have accumulated that support that idea that APP is a functional receptor linked to a Go signaling cascade. Apoptosis is induced in neuronal cells expressing FAD mutants of APP, and this phenotype is independent of the production of Aβ1–42. Expression of FAD

Acknowledgements

We thank Dawn Morrissey for assistance in preparation of the manuscript. The work from our laboratory that is described in this review was funded by NIH grant AG12954.

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