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

Background Amyloid-β (Aβ) and tau pathology are key molecular hallmarks of Alzheimer’s disease (AD), yet how their interaction contributes to cognitive decline remains unclear. We investigated the relationship between Aβ burden, tau pathology, presynaptic density, and spatial learning and memory in the APPswe/PSEN1ΔE9 (APP/PS1) transgenic (TG) mouse model of amyloidosis.

Spatial 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 Aβ plaque load was measured by immunohistochemistry. Correlation and linear mixed-effects regression analyses were used to assess relationships between behavioral and pathological measures.

APP/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 Aβ 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 Aβ and tau pathology across all areas examined. Linear regression revealed a significant association between tau and age and between tau and Aβ in the cortex, indicating that memory decline in ageing TG mice was driven by the combined effects of these pathologies.

Deficits 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 Aβ-tau interaction observed in human AD. Competing Interest Statement The authors have declared no competing interest.