Abstract
The amyloid cascade hypothesis posits that deposition of the amyloid β (Aβ) peptide in the brain is a key event in the initiation of Alzheimer's disease (AD). Nonetheless, it now seems increasingly unlikely that amyloid toxicity is the cause of sporadic AD, which leads to cognitive decline. Here, using accelerated-senescence nontransgenic OXYS rats, we confirmed that aggregation of Aβ is a later event in AD-like pathology. We showed that an age-dependent increase in the levels of Aβ₁₋₄₂ and extracellular Aβ deposits in the brain of OXYS rats occur later than do synaptic losses, neuronal cell death, mitochondrial structural abnormalities, and hyperphosphorylation of the tau protein. We identified the variants of the genes that are strongly associated with the risk of either late-onset or early-onset AD, including App, Apoe4, Bace1, Psen1, Psen2, and Picalm. We found that in OXYS rats nonsynonymous SNPs were located only in the genes Casp3 and Sorl1. Thus, we present proof that OXYS rats may be a model of sporadic AD. It is possible that multiple age-associated pathological processes may precede the toxic amyloid accumulation, which in turn triggers the final stage of the sporadic form of AD and becomes a hallmark event of the disease.
Highlights
Alzheimer’s disease (AD) is the most common type of age-related dementia worldwide, with dramatically increasing incidence as a consequence of ageing of the population
According to the amyloid hypothesis, which dominated the research of AD pathogenesis for more than 20 years, accumulation of soluble amyloid β (Aβ) into toxic oligomers and amyloid plaques initiates a pathogenic cascade leading to accumulation of the hyperphosphorylated tau protein in neurofibrillary tangles, to mitochondrial dysfunction, loss of synapses, neuronal cell death, and, a loss of cognitive function [1,2,3]
We explored the role of Aβ in the pathogenesis of AD by analyzing the age-dependent profile of Aβ species in a nontransgenic rat model of AD
Summary
Alzheimer’s disease (AD) is the most common type of age-related dementia worldwide, with dramatically increasing incidence as a consequence of ageing of the population. According to the amyloid hypothesis, which dominated the research of AD pathogenesis for more than 20 years, accumulation of soluble amyloid β (Aβ) into toxic oligomers and amyloid plaques initiates a pathogenic cascade leading to accumulation of the hyperphosphorylated tau protein in neurofibrillary tangles, to mitochondrial dysfunction, loss of synapses, neuronal cell death, and, a loss of cognitive function [1,2,3] The evidence supporting this hypothesis includes genetic effects of the dominantly inherited familial earlyonset form of AD, which accounts for ~5% of all cases, involving mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1), or PSEN2 genes [4]. Alternative explanations are that sporadic AD dementia is not the result of a single cause but rather of multiple age-associated processes that erode brain structure and function gradually, making it vulnerable to degeneration; combined with the conditions that trigger the events of AD, the above processes result in accelerated neuronal and synaptic losses and in cognitive decline [2]
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