THE GENETICS AND MOLECULAR PATHOLOGY OF ALZHEIMER'S DISEASE: Roles of Amyloid and the Presenilins
Section snippets
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
References (94)
- et al.
Hydrogen peroxide mediates amyloid β protein toxicity
Cell
(1994) - et al.
Co-expression of β-amyloid precursor protein (βAPP) and apolipoprotein E in cell culture: Analysis of βAPP processing
Neurobiology of Disease
(1995) - et al.
Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor
J Biol Chem
(1998) - et al.
β-Amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease
Neurobiology of Aging
(1996) - et al.
Inflammatory mechanisms in Alzheimer's disease
Trends Pharmacol Sci
(1994) - et al.
Alzheimer's disease and Down's syndrome: Sharing of a unique cerebrovascular amyloid fibril protein
Biochem Biophys Res Commun
(1984) - et al.
Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein
Biochem Biophys Res Commun
(1984) Tau mutations cause frontotemporal dementias
Neuron
(1998)- et al.
Intraneuronal Aβ42 accumulation in human brain
Am J Pathol
(2000) - et al.
Direct evidence of oxidative injury produced by the Alzheimer's beta-amyloid peptide (1-40) in cultured hippocampal neurons
Exp Neurol
(1995)
Ultrastructural localization of complement membrane attack complex (MAC)-like immunoreactivity in brains of patients with Alzheimer's disease
Brain Res
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
The transmembrane aspartates in presenilin 1 and 2 are obligatory for γ-secretase activity and amyloid β-protein generation
J Biol Chem
Sequence of deposition of heterogeneous amyloid β-peptides and Apo E in Down syndrome: Implications for initial events in amyloid plaque formation
Neurobiol Disease
The inflammatory response system of brain: Implications for therapy of Alzheimer and other neurodegenerative diseases
Brain Res Rev
Effects of PS1 deficiency on membrane protein trafficking in neurons
Neuron
Inflammation and Alzheimer's disease pathogenesis
Neurobiol Aging
Notch and presenilins in vertebrates and invertebrates: Implications for neuronal development and degeneration
Curr Opin Neurobiol
Skeletal and CNS defects in presenilin-1 deficient mice
Cell
Expression of a ubiquitous, cross-reactive homologue of the mouse β-amyloid precursor protein (APP)
J Biol Chem
Preamyloid deposits in the cerebral cortex of patients with Alzheimer's disease and nondemented individuals
Neurosci Lett
Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo
Neuron
Stable association of presenilin derivatives and absence of presenilin interactions with APP
Neurobiol Dis
β-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity
Cell
Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition
Nat Genet
A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells
Nature
Alpha-2 macroglobulin is genetically associated with Alzheimer disease
Nat Genet
Caspasse-mediated cleavage is not required for the activity of presenilins in amyloidogenesis and NOTCH signaling
NeuroReport
A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain
Nature
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
Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein
Nature
The neurofibrillary pathology of Alzheimer's disease
Abnormal phosphorylation of the microtubule-associated protein t (tau) in Alzheimer cytoskeletal pathology
Proc Natl Acad Sci USA
Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid β-protein precursor
J Biol Chem
Amyloid β-peptide is produced by cultured cells during normal metabolism
Nature
Plaque-only Alzheimer disease is usually the Lewy body variant, and vice versa
J Neuropathol Exp Neurol
Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene
Nat Genet
Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes
Nat Med
Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17
Science
Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice
Science
Association of missense and 5′-splice-site mutations in tau with the inherited FTDP-17
Nature
The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Nature
Microtubule-associated protein, tau, is a major antigenic component of paired helical filaments in Alzheimer's disease
Proc Natl Acad Sci USA
Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins
Proc Natl Acad Sci USA
The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology
Nat Med
Assessment of normal and mutant human presenilin function in Caenorhabditis elegans
Proc Natl Acad Sci USA
Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch-type
Science
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2016, Experimental NeurologyCitation Excerpt :While early research suggested that these plaques may be the cause of cognitive dysfunction in AD, recent work indicates that cognitive deficits in AD occur even in the absence of plaques (Yamaguchi et al., 1991; Van Dam et al., 2003). It is now widely believed that the accumulation of soluble Aβ is central to the pathogenesis of the disease (Selkoe, 2000). Soluble Aβ oligomers have been shown to induce many of the deficits associated with AD (Shankar et al., 2008; Logan et al., 2011; Miñano-Molina et al., 2011; Reese et al., 2011; Tan et al., 2011; Ferreira et al., 2012).
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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]
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Department of Neurology and Neuroscience, Harvard Medical School; and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts