A systematic review and meta-analysis of tau phosphorylation in mouse models of familial Alzheimer’s disease

Abstract

Abstract Background Transgenic models of familial Alzheimer’s disease (AD) serve as valuable tools for probing the molecular mechanisms associated with amyloid-beta (Aβ)-induced pathology. Here, we sought to evaluate the levels of phosphorylated tau (p-tau) protein, and explore potential age-related variations in the hyperphosphorylation of tau, in mouse models of cerebral amyloidosis. Methods The PubMed and Scopus databases were searched for studies measuring soluble p-tau in 5xFAD, APP swe / PSEN1 de9 , J20 and APP23 mice. Data were extracted and analyzed using standardized procedures. Results For the 5xFAD model, the search yielded 36 studies eligible for meta-analysis. Levels of p-tau were higher in 5xFAD mice relative to control, a difference that was evident in both the carboxy-terminal (CT) and proline-rich (PR) domains of tau. Age negatively moderated the effects of genotype on CT domain phosphorylated tau, particularly in studies using hybrid mice, female mice, and preparations from the cortex. For the APP swe / PSEN1 de9 model, the search yielded 27 studies. Analysis showed tau hyperphosphorylation in transgenic vs. control animals, evident in both the CT and PR regions of tau. Age positively moderated the effects of genotype on PR domain phosphorylated tau in the cortex of APP swe / PSEN1 de9 mice. A meta-analysis was not performed for the J20 and APP23 models, due to the limited number of studies measuring p-tau levels in these mice (<10 studies). Conclusions Although tau is hyperphosphorylated in both 5xFAD and APP swe / PSEN1 de9 mice, the effects of ageing on p-tau are contingent upon the mouse model being examined. These observations emphasize the importance of tailoring model selection to the appropriate disease stage when assessing the relationship between Aβ and tau, and suggest that there are optimal intervention points for the administration of both anti-amyloid and anti-tau therapies.