Abstract
Despite compelling evidence that the accumulation of amyloid-beta (Aβ) promotes neocortical MAPT (tau) aggregation in familial and idiopathic Alzheimer’s disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. In the present study, we show that tau can accumulate spontaneously in aged transgenic APPswe/PS1ΔE9 mice. Tau pathology is abundant around Aβ deposits, and further characterized by accumulation of Gallyas and thioflavin-S-positive inclusions, which were detected in the APPswe/PS1ΔE9 brain at 18 months of age. Age-dependent increases in argyrophilia correlated positively with binding levels of the paired helical filament (PHF) tracer [18F]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Quantitative proteomics identified sequences of hyperphosphorylated and three-repeat tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Tissue from the frontal gyrus of human subjects was used to validate these findings, revealing primarily quantitative differences between the tau pathology observed in AD patient vs. transgenic mouse tissue. As physiological levels of endogenous, ‘wild-type’ tau aggregate secondarily to Aβ in APPswe/PS1ΔE9 mice, this study suggests that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.
Highlights
Despite compelling evidence that the accumulation of amyloid-beta (Aβ) promotes neocortical MAPT aggregation in familial and idiopathic Alzheimer’s disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology
Transgenic mouse models that reproduce the amyloid aggregation and glial activation due to Aβ overexpression have been generated based on mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) and 2 (PSEN2) genes, which are known to cause familial AD1
A third reason that is often cited for the absence of tau pathology in amyloidosis models is that the murine lifespan may be too short for the complete sequence of neurofibrillary pathology to unfold in transgenic mice[25]
Summary
Despite compelling evidence that the accumulation of amyloid-beta (Aβ) promotes neocortical MAPT (tau) aggregation in familial and idiopathic Alzheimer’s disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. We show that tau can accumulate spontaneously in aged transgenic APPswe/PS1ΔE9 mice. As physiological levels of endogenous, ‘wild-type’ tau aggregate secondarily to Aβ in APPswe/PS1ΔE9 mice, this study suggests that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD. Hallmark post-translational modifications (PTMs) that are associated with the accumulation of fibrillar tau in AD, such as phosphorylation[23], have been detected in the brain of transgenic mice[24], including APPswe/PS1ΔE9 mice (Supplementary Table S1). The present study was based on evidence that murine tau aggregates into paired helical filaments (PHFs) in vitro, becoming hyperphosphorylated during the course of amyloidosis in the transgenic mouse brain. These results show that it is possible to model the relationship between aberrant APP processing and tau pathology in a translationally-relevant manner
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