Characterization of a Mouse Model of Alzheimer's Disease Expressing Aβ4-42 and Human Mutant Tau.

Silvia Zampar,Oliver Wirths

doi:10.3390/ijms22105191

Silvia Zampar, Oliver Wirths

Open Access

https://doi.org/10.3390/ijms22105191

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Abstract

The relationship between the two most prominent neuropathological hallmarks of Alzheimer’s Disease (AD), extracellular amyloid-β (Aβ) deposits and intracellular accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFT), remains at present not fully understood. A large body of evidence places Aβ upstream in the cascade of pathological events, triggering NFTs formation and the subsequent neuron loss. Extracellular Aβ deposits were indeed causative of an increased tau phosphorylation and accumulation in several transgenic models but the contribution of soluble Aβ peptides is still controversial. Among the different Aβ variants, the N-terminally truncated peptide Aβ4–42 is among the most abundant. To understand whether soluble Aβ4–42 peptides impact the onset or extent of tau pathology, we have crossed the homozygous Tg4–42 mouse model of AD, exclusively expressing Aβ4–42 peptides, with the PS19 (P301S) tau transgenic model. Behavioral assessment showed that the resulting double-transgenic line presented a partial worsening of motor performance and spatial memory deficits in the aged group. While an increased loss of distal CA1 pyramidal neurons was detected in young mice, no significant alterations in hippocampal tau phosphorylation were observed in immunohistochemical analyses.

Highlights

IntroductionAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that is histopathologically characterized by the deposition of extracellular senile plaques containing amyloid-β (Aβ) protein [1], as well as the intracellular accumulation of so-called neurofibrillary tangles (NFTs) consisting of hyperphosphorylated protein tau [2]
While Aβ peptides are derived from proteolytical cleavage events of the transmembrane amyloid precursor protein (APP), tau proteins are brain-specific microtubule-associated molecules enriched in axons
Body weight of the transgenic lines did not differ compared to WT littermates, and no significant changes were observed between

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is histopathologically characterized by the deposition of extracellular senile plaques containing amyloid-β (Aβ) protein [1], as well as the intracellular accumulation of so-called neurofibrillary tangles (NFTs) consisting of hyperphosphorylated protein tau [2]. While Aβ peptides are derived from proteolytical cleavage events of the transmembrane amyloid precursor protein (APP), tau proteins are brain-specific microtubule-associated molecules enriched in axons. A variety of studies employing mainly transgenic AD mouse models investigated the relationship between both pathological hallmarks. According to the amyloid cascade hypothesis, a disequilibrium of Aβ production and clearance is regarded as an upstream event entailing the formation of NFTs and the subsequent loss of synapses and neurons [3].

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