Elsevier

Neurologic Clinics

Volume 18, Issue 4, 1 November 2000, Pages 903-921
Neurologic Clinics

THE GENETICS AND MOLECULAR PATHOLOGY OF ALZHEIMER'S DISEASE: Roles of Amyloid and the Presenilins

https://doi.org/10.1016/S0733-8619(05)70232-2Get rights and content

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THE BIOCHEMICAL NATURE OF THE CLASSIC BRAIN LESIONS

Much of the progress in elucidating the biology of AD has derived from the original compositional analyses of the amyloid plaques and neurofibrillary tangles in the mid 1980s. Early attempts to purify the tangle and plaque subunit proteins were met with some skepticism; as it was argued that because the plaques and tangles were end-stage lesions that appeared to represent the tombstones of the pathogenic process, such knowledge would provide little useful information about etiology and early

HOW Aβ IS PRODUCED FROM ITS LARGE PRECURSOR PROTEIN

The purification and partial sequencing of the Aβ protein from meningovascular amyloid deposits in AD14 and Down syndrome13 enabled the subsequent cloning of the gene encoding the β-amyloid precursor protein (APP).30 Aβ is too small to be synthesized directly on ribosomes; rather, it is derived from APP by sequential proteolytic cleavages by enzyme activities referred to as β-secretase and γ-secretase (reviewed in reference 63). APP comprises a group of ubiquitously expressed polypeptides whose

THE GENETICS OF ALZHEIMER'S DISEASE

It has been known for several decades that AD can occur in a familial form that appears to be transmitted as an autosomal dominant trait. Estimates of the proportion of AD cases that are genetically based have varied widely from as low as 10% to as high as 40% or 50%, and some investigators believe that, in the fullness of time, virtually all cases will be shown to have genetic determinants. It is difficult to settle this question in a disorder that can have very late onset in life and that was

DECIPHERING THE GENOTYPE TO PHENOTYPE CONVERSIONS OF FAMILIAL ALZHEIMER'S DISEASE

What do the last two sections in this review have to do with each other? That is, is there a relationship between the genetic factors that have been proved unequivocally to cause AD in some individuals and the production or stability of Aβ? Research by many investigators worldwide during the last 7 years has provided answers to these questions. Both cultured cells and transgenic mice have been used to model the biochemical and neuropathologic effects of each of the four genes implicated

THE COMPLEX PATHOGENETIC CASCADE OF AD

Although genetic evidence has strongly favored the concept that Aβ production and accumulation are early and essential features of AD, there remains much debate about whether and how this finding can explain the full Alzheimer phenotype. Gradual and chronic elevation of Aβ42 in brain interstitial fluid (and perhaps also inside neurons72, 82a) caused by mutations in APP or presenilin is assumed to lead gradually to oligomerization of some of the peptide and then, eventually, its fibrillization

QUESTIONS ABOUND

Although genetic, neuropathologic, cell culture, and animal modeling studies all support an Aβ-mediated cytopathologic cascade along the lines of that suggested in the previous section, many questions remain unanswered. One would like to know the relative contributions of extracellular and intraneuronal Aβ accumulation in potentially initiating neurotoxicity. Whereas immunohistochemistry has traditionally shown only abundant extracellular Aβ deposits in AD brain, very recent evidence suggests

THERAPEUTIC OPPORTUNITIES AND THEIR APPLICATION TO PATIENTS

The recent progress in illuminating the role of the presenilins in the proteolytic processing of APP, Notch, and perhaps other important cellular proteins gives rise to a new way of thinking about the origin of AD. It appears that the presenilins and, in particular, their two transmembrane aspartates were conserved during evolution because they confer a strong developmental advantage in mediating the Notch signaling pathway that is vital for life. The formation of stable complexes between Notch

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References (94)

  • S. Itagaki et al.

    Ultrastructural localization of complement membrane attack complex (MAC)-like immunoreactivity in brains of patients with Alzheimer's disease

    Brain Res

    (1994)
  • T. Iwatsubo et al.

    Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: Evidence that an initially deposited species is A beta 42(43)

    Neuron

    (1994)
  • W.T. Kimberly et al.

    The transmembrane aspartates in presenilin 1 and 2 are obligatory for γ-secretase activity and amyloid β-protein generation

    J Biol Chem

    (2000)
  • C.A. Lemere et al.

    Sequence of deposition of heterogeneous amyloid β-peptides and Apo E in Down syndrome: Implications for initial events in amyloid plaque formation

    Neurobiol Disease

    (1996)
  • P.L. McGeer et al.

    The inflammatory response system of brain: Implications for therapy of Alzheimer and other neurodegenerative diseases

    Brain Res Rev

    (1995)
  • S. Naruse et al.

    Effects of PS1 deficiency on membrane protein trafficking in neurons

    Neuron

    (1998)
  • J. Rogers et al.

    Inflammation and Alzheimer's disease pathogenesis

    Neurobiol Aging

    (1996)
  • D.J. Selkoe

    Notch and presenilins in vertebrates and invertebrates: Implications for neuronal development and degeneration

    Curr Opin Neurobiol

    (2000)
  • J. Shen et al.

    Skeletal and CNS defects in presenilin-1 deficient mice

    Cell

    (1997)
  • H.H. Slunt et al.

    Expression of a ubiquitous, cross-reactive homologue of the mouse β-amyloid precursor protein (APP)

    J Biol Chem

    (1994)
  • F. Tagliavini et al.

    Preamyloid deposits in the cerebral cortex of patients with Alzheimer's disease and nondemented individuals

    Neurosci Lett

    (1988)
  • G. Thinakaran et al.

    Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo

    Neuron

    (1996)
  • G. Thinakaran et al.

    Stable association of presenilin derivatives and absence of presenilin interactions with APP

    Neurobiol Dis

    (1998)
  • H. Zheng et al.

    β-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity

    Cell

    (1995)
  • K.R. Bales et al.

    Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition

    Nat Genet

    (1997)
  • R.A. Black et al.

    A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells

    Nature

    (1997)
  • D. Blacker et al.

    Alpha-2 macroglobulin is genetically associated with Alzheimer disease

    Nat Genet

    (1998)
  • M. Brockhaus et al.

    Caspasse-mediated cleavage is not required for the activity of presenilins in amyloidogenesis and NOTCH signaling

    NeuroReport

    (1998)
  • De StrooperB. et al.

    A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain

    Nature

    (1999)
  • K.C. Evans et al.

    Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: Implications for the pathogenesis and treatment of Alzheimer disease

    Proc Natl Acad Sci USA

    (1995)
  • D. Games et al.

    Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein

    Nature

    (1995)
  • M. Goedert et al.

    The neurofibrillary pathology of Alzheimer's disease

  • I. Grundke-Iqbal et al.

    Abnormal phosphorylation of the microtubule-associated protein t (tau) in Alzheimer cytoskeletal pathology

    Proc Natl Acad Sci USA

    (1986)
  • C. Haas et al.

    Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid β-protein precursor

    J Biol Chem

    (1994)
  • C. Haass et al.

    Amyloid β-peptide is produced by cultured cells during normal metabolism

    Nature

    (1992)
  • L.A. Hansen et al.

    Plaque-only Alzheimer disease is usually the Lewy body variant, and vice versa

    J Neuropathol Exp Neurol

    (1993)
  • HendriksL. et al.

    Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene

    Nat Genet

    (1992)
  • L. Holcomb et al.

    Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes

    Nat Med

    (1998)
  • M. Hong et al.

    Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17

    Science

    (1998)
  • K. Hsiao et al.

    Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice

    Science

    (1996)
  • M. Hutton et al.

    Association of missense and 5′-splice-site mutations in tau with the inherited FTDP-17

    Nature

    (1998)
  • KangJ. et al.

    The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor

    Nature

    (1987)
  • K.S. Kosik et al.

    Microtubule-associated protein, tau, is a major antigenic component of paired helical filaments in Alzheimer's disease

    Proc Natl Acad Sci USA

    (1986)
  • M.P. Lambert et al.

    Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins

    Proc Natl Acad Sci USA

    (1998)
  • C.A. Lemere et al.

    The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology

    Nat Med

    (1996)
  • D. Levitan et al.

    Assessment of normal and mutant human presenilin function in Caenorhabditis elegans

    Proc Natl Acad Sci USA

    (1996)
  • E. Levy et al.

    Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch-type

    Science

    (1990)
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    Address reprint requests to Dennis J. Selkoe, MD, Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115, [email protected]

    *

    Department of Neurology and Neuroscience, Harvard Medical School; and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts

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