Insights into Alzheimer disease pathogenesis from studies in transgenic animal models

Abstract

Alzheimer disease is the most common cause of dementia among the elderly, accounting for ∼60-70% of all cases of dementia. The neuropathological hallmarks of Alzheimer disease are senile plaques (mainly containing β-amyloid peptide derived from amyloid precursor protein) and neurofibrillary tangles (containing hyperphosphorylated Tau protein), along with neuronal loss. At present there is no effective treatment for Alzheimer disease. Given the prevalence and poor prognosis of the disease, the development of animal models has been a research priority to understand pathogenic mechanisms and to test therapeutic strategies. Most cases of Alzheimer disease occur sporadically in people over 65 years old, and are not genetically inherited. Roughly 5% of patients with Alzheimer disease have familial Alzheimer disease—that is, related to a genetic predisposition, including mutations in the amyloid precursor protein, presenilin 1, and presenilin 2 genes. The discovery of genes for familial Alzheimer disease has allowed transgenic models to be generated through the overexpression of the amyloid precursor protein and/or presenilins harboring one or several mutations found in familial Alzheimer disease. Although none of these models fully replicates the human disease, they have provided valuable insights into disease mechanisms as well as opportunities to test therapeutic approaches. This review describes the main transgenic mouse models of Alzheimer disease which have been adopted in Alzheimer disease research, and discusses the insights into Alzheimer disease pathogenesis from studies in such models. In summary, the Alzheimer disease mouse models have been the key to understanding the roles of soluble β-amyloid oligomers in disease pathogenesis, as well as of the relationship between β-amyloid and Tau pathologies.

Animal models of Alzheimer disease: historical pitfalls and a path forward

“…Additionally, the mice develop other pathological and behavioral characteristics similar to AD: gliosis, synaptic damage and memory impairment (Oddo et al, 2003). These mice further support the notion that soluble Aβ oligomers are toxic, as neuronal and functional deficits appear prior to plaque or NFT formation (Morrissette et al, 2009;Schaeffer et al, 2011). While the transgenic mice described above have been very widely used in AD research, a number of other transgenic and non-transgenic animal models have been developed as well.…”

“…Use of transgenic mouse models of amyloid pathology has led to new insights regarding the processing of Aβ and the role of soluble Aβ oligomers in the pathogenesis of AD (Schaeffer et al, 2011;Morrissette et al, 2009;Cheng et al, 2007;Lesne et al, 2006). For example, in many APP transgenic mice, pathological and functional changes occur before the appearance of amyloid plaques (Schaeffer et al, 2011).…”

“…For example, in many APP transgenic mice, pathological and functional changes occur before the appearance of amyloid plaques (Schaeffer et al, 2011).…”

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“…Concurrently, they show increased levels of both Ab and Ab in their parenchyma and a reduced performance of spatial working memory in the period preceding overt Ab deposition [5]. Such findings support a critical role of Ab in the pathogenesis of AD and suggest a neurotoxic effect of soluble forms of Ab as well [6].…”

“…We conducted an analysis of mouse brain homogenates using monoclonal Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] antibody (6E10) to analyze Ab species and b-C-terminal fragments (b-CTFs), from both the 6-and 10-month treated groups. The 6E10 antibody specifically recognizes APP and b-CTFs.…”