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Ageing and amyloidosis underlie the molecular and pathological alterations of tau in a mouse model of familial Alzheimer's disease.

ABSTRACT: Despite compelling evidence that the accumulation of amyloid-beta (A?) 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/PS1?E9 mice. Tau pathology is abundant around A? deposits, and further characterized by accumulation of Gallyas and thioflavin-S-positive inclusions, which were detected in the APPswe/PS1?E9 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 A? in APPswe/PS1?E9 mice, this study suggests that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.

SUBMITTER: Metaxas A

PROVIDER: S-EPMC6823454 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Ageing and amyloidosis underlie the molecular and pathological alterations of tau in a mouse model of familial Alzheimer's disease.

Metaxas Athanasios A Thygesen Camilla C Kempf Stefan J SJ Anzalone Marco M Vaitheeswaran Ramanan R Petersen Sussanne S Landau Anne M AM Audrain Hélène H Teeling Jessica L JL Darvesh Sultan S Brooks David J DJ Larsen Martin R MR Finsen Bente B

Scientific reports 20191031 1

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 APP<sub>swe</sub>/PS1<sub>ΔE9</sub> mice. Tau pathology is abundant around Aβ deposits, and further characterized by accumulation of Gallyas and thiofl ...[more]

PMID: 31673052

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Project description:See Hansson and Mormino (doi:10.1093/brain/awy065) for a scientific commentary on this article.Our objective was to compare different whole-brain and region-specific measurements of within-person change on serial tau PET and evaluate its utility for clinical trials. We studied 126 individuals: 59 cognitively unimpaired with normal amyloid, 37 cognitively unimpaired with abnormal amyloid, and 30 cognitively impaired with an amnestic phenotype and abnormal amyloid. All had baseline amyloid PET and two tau PET, MRI, and clinical assessments. We compared the topography across all cortical regions of interest of tau PET accumulation rates and the rates of four different whole-brain or region-specific meta-regions of interest among the three clinical groups. We computed sample size estimates for change in tau PET, cortical volume, and memory/mental status indices for use as outcome measures in clinical trials. The cognitively unimpaired normal amyloid group had no observable tau accumulation throughout the brain. Tau accumulation rates in cognitively unimpaired abnormal amyloid were low [0.006 standardized uptake value ratio (SUVR), 0.5%, per year] but greater than rates in the cognitively unimpaired normal amyloid group in the basal and mid-temporal, retrosplenial, posterior cingulate, and entorhinal regions of interest. Thus, the earliest elevation in accumulation rates was widespread and not confined to the entorhinal cortex. Tau accumulation rates in the cognitively impaired abnormal amyloid group were 0.053 SUVR (3%) per year and greater than rates in cognitively unimpaired abnormal amyloid in all cortical areas except medial temporal. Rates of accumulation in the four meta-regions of interest differed but only slightly from one another. Among all tau PET meta-regions of interest, sample size estimates were smallest for a temporal lobe composite within cognitively unimpaired abnormal amyloid and for the late Alzheimer's disease meta-region of interest within cognitively impaired abnormal amyloid. The ordering of the sample size estimates by outcome measure was MRI < tau PET < cognitive measures. At a group-wise level, observable rates of short-term serial tau accumulation were only seen in the presence of abnormal amyloid. As disease progressed to clinically symptomatic stages (cognitively impaired abnormal amyloid), observable rates of tau accumulation were seen uniformly throughout the brain providing evidence that tau does not accumulate in one area at a time or in start-stop, stepwise sequence. The information captured by rate measures in different meta-regions of interest, even those with little topographic overlap, was similar. The implication is that rate measurements from simple meta-regions of interest, without the need for Braak-like staging, may be sufficient to capture progressive within-person accumulation of pathologic tau. Tau PET SUVR measures should be an efficient outcome measure in disease-modifying clinical trials.

Dataset Information

Ageing and amyloidosis underlie the molecular and pathological alterations of tau in a mouse model of familial Alzheimer's disease.

Publications

Ageing and amyloidosis underlie the molecular and pathological alterations of tau in a mouse model of familial Alzheimer's disease.

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