Alzheimer's Disease: The Amyloid Cascade Hypothesis

Hardy, John; Higgins, Gerald A.

doi:10.1126/science.1566067

Cited by 5,955 publications

(4,201 citation statements)

References 54 publications

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“…In the brain, ApoE plays a role in astrocyte‐mediated amyloid‐beta degradation (Koistinaho et al., 2004), supporting the amyloid cascade hypothesis of AD development (Hardy & Higgins, 1992). However, some researchers contend that variants of other genes in the APOE region play a role in AD development.…”

Section: Introductionsupporting

confidence: 64%

Apolipoprotein E region molecular signatures of Alzheimer's disease

et al. 2018

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SummaryAlthough the APOE region is the strongest genetic risk factor for Alzheimer's diseases (ADs), its pathogenic role remains poorly understood. Elucidating genetic predisposition to ADs, a subset of age‐related diseases characteristic for postreproductive period, is hampered by the undefined role of evolution in establishing molecular mechanisms of such diseases. This uncertainty is inevitable source of natural‐selection–free genetic heterogeneity in predisposition to ADs. We performed first large‐scale analysis of linkage disequilibrium (LD) structures characterized by 30 polymorphisms from five genes in the APOE 19q13.3 region (BCAM,NECTIN2,TOMM40,APOE, and APOC1) in 2,673 AD‐affected and 16,246 unaffected individuals from five cohorts. Consistent with the undefined role of evolution in age‐related diseases, we found that these structures, being highly heterogeneous, are significantly different in subjects with and without ADs. The pattern of the difference represents molecular signature of AD comprised of single nucleotide polymorphisms (SNPs) from all five genes in the APOE region. Significant differences in LD in subjects with and without ADs indicate SNPs from different genes likely involved in AD pathogenesis. Significant and highly heterogeneous molecular signatures of ADs provide unprecedented insight into complex polygenetic predisposition to ADs in the APOE region. These findings are more consistent with a complex haplotype than with a single genetic variant origin of ADs in this region.

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Section: Introductionsupporting

confidence: 64%

Apolipoprotein E region molecular signatures of Alzheimer's disease

et al. 2018

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“…The accumulation of Aβ, and especially its longer forms (e.g., ~42 aa), within plaques, together with Tau tangles, are the neuropathological hallmarks of AD. The deleterious effects of Aβ deposition during the symptomatic stages of AD are undeniable (Hardy & Higgins, 1992), but the role of Aβ in earlier phases of the disease is still debated.…”

Section: Introductionmentioning

confidence: 99%

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

et al. 2017

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In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β‐secretase to generate a 99‐aa C‐terminal fragment (C99) that is then cleaved by γ‐secretase to generate the β‐amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ‐secretase activity is enriched in mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM) and that ER–mitochondrial connectivity and MAM function are upregulated in AD. We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ‐secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.

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“…Pathological accumulation of β‐amyloid (Aβ) is the feature of AD (Hardy & Allsop, 1991; Selkoe, 1991; Hardy & Higgins, 1992). Specifically, soluble Aβ oligomers are fundamental to promote neurotoxicity (Klein, 2001; Walsh & Selkoe, 2007) through different ways (Ferreira & Klein, 2011; Pearson‐Leary & McNay, 2012), including altered levels of neurotrophic factors (NTFs) (Calissano et al ., 2010; Budni et al ., 2015).…”

Section: Introductionmentioning

confidence: 99%

Amyloid Beta monomers regulate cyclic adenosine monophosphate response element binding protein functions by activating type‐1 insulin‐like growth factor receptors in neuronal cells

et al. 2017

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SummaryAlzheimer's disease (AD) is a progressive neurodegenerative disorder associated with synaptic dysfunction, pathological accumulation of β‐amyloid (Aβ), and neuronal loss. The self‐association of Aβ monomers into soluble oligomers seems to be crucial for the development of neurotoxicity (J. Neurochem., 00, 2007 and 1172). Aβ oligomers have been suggested to compromise neuronal functions in AD by reducing the expression levels of the CREB target gene and brain‐derived neurotrophic factor (BDNF) (J. Neurosci., 27, 2007 and 2628; Neurobiol. Aging, 36, 2015 and 20406 Mol. Neurodegener., 6, 2011 and 60). We previously reported a broad neuroprotective activity of physiological Aβ monomers, involving the activation of type‐1 insulin‐like growth factor receptors (IGF‐IRs) (J. Neurosci., 29, 2009 and 10582, Front Cell Neurosci., 9, 2015 and 297). We now provide evidence that Aβ monomers, by activating the IGF‐IR‐stimulated PI3‐K/AKT pathway, induce the activation of CREB in neurons and sustain BDNF transcription and release.

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Alzheimer's Disease: The Amyloid Cascade Hypothesis

Cited by 5,955 publications

References 54 publications

Apolipoprotein E region molecular signatures of Alzheimer's disease

Apolipoprotein E region molecular signatures of Alzheimer's disease

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

Amyloid Beta monomers regulate cyclic adenosine monophosphate response element binding protein functions by activating type‐1 insulin‐like growth factor receptors in neuronal cells

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