Vaitheeswaran, R. | bioRxiv Science

bioRxiv2025

Age-specific Aβ-Tau interactions underlie spatial memory deficits in an APP/PS1 amyloidosis model

BackgroundAmyloid-{beta} (A{beta}) and tau pathology are key molecular hallmarks of Alzheimers disease (AD), yet how their interaction contributes to cognitive decline remains unclear. We investigated the relationship between A{beta} burden, tau pathology, presynaptic density, and spatial learning and memory in the APPswe/PSEN1{Delta}E9 (APP/PS1) transgenic (TG) mouse model of amyloidosis. MethodsSpatial learning and memory were assessed with the Barnes maze test in male TG and wild-type (WT) littermate mice, aged 6, 12, and 18 months. Gross visual function was assessed indirectly in 18-month-old animals using the light/dark exploration test. Brains were collected for autoradiography of tau pathology and presynaptic density with [18F]Flortaucipir and [3H]UCB-J, respectively, while A{beta} plaque load was measured by immunohistochemistry. Correlation and linear mixed-effects regression analyses were used to assess relationships between behavioral and pathological measures. ResultsAPP/PS1 mice showed normal cognitive performance at 6 months, a selective long-term memory deficit at 12 months, and severe impairments in learning and retention at 18 months, independent of visual confounds. Age-dependent increases in [18F]Flortaucipir binding and A{beta} plaque load were observed in all brain regions of TG compared to WT mice, whereas [3H]UCB-J binding was increased in a region-dependent manner in 18-month-old TG vs. WT animals. Barnes maze performance during the final day of testing correlated negatively with both A{beta} and tau pathology across all areas examined. Linear regression revealed a significant association between tau and age and between tau and A{beta} in the cortex, indicating that memory decline in ageing TG mice was driven by the combined effects of these pathologies. ConclusionsDeficits in memory retention precede impairments in task learning performance in APP/PS1 mice. Spontaneous tau accumulation contributes to the progressive cognitive decline, capturing key aspects of the A{beta}-tau interaction observed in human AD.

neuroscience↗

bioRxiv2018

Tauopathy in the APPswe/PS1ΔE9 mouse model of familial Alzheimer’s disease

Despite compelling evidence that the accumulation of amyloid-beta (A{beta}) promotes cortical MAPT (tau) aggregation in familial and idiopathic Alzheimers disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. The absence of neurofibrillary lesions in amyloidosis mice remains a challenge for the amyloidocentric paradigm of AD pathogenesis. It has resulted in the generation of transgenic mice harboring mutations in their tau gene, which may be inappropriate for studying a disease with no known TAU mutations, such as AD. Here, we have used APPswe/PS1{Delta}E9 mice to show that tau pathology can develop spontaneously in murine models of familial AD. Tauopathy was abundant around A{beta} deposits, with Gallyas- and thioflavin-S-positive perinuclear inclusions accumulating in the APPswe/PS1{Delta}E9 cortex by 18 months of age. Age-dependent increases in Gallyas signal correlated positively with binding levels of the paired helical filament (PHF) ligand [18F]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Tandem mass tag proteomics identified sequences of hyperphosphorylated tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Human frontal gyrus tissue was used to validate these findings, revealing primarily quantitative differences between the tauopathy observed in AD patient vs. transgenic mouse tissue. Levels of tau mRNA were not different between APPswe/PS1{Delta}E9 and littermate control animals. As physiological levels of endogenous, wild-type tau aggregate secondarily to A{beta} in transgenic mice, this study demonstrates that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.

neuroscience↗