Links between memory, synapses, amyloid-beta, tau and microglial changes after tau pathology induction by Alzheimer’s brain inoculation in amyloid-beta-plaque bearing mice

Background: Alzheimer’s disease (AD) is characterized by the presence of both extracellular amyloid-β (Aβ) plaques and intracellular tau accumulations. The causative interactions between these lesions, and the subsequent neuroinflammation, synaptic alterations and memory impairment are still debated. Intracerebral infusion of human AD brain extracts in Aβ bearing mice that do not overexpress pathological tau proteins induces widespread Aβ and tau pathologies following heterotopic seeding of mouse tau. These models provide a unique opportunity to assess relationships between AD lesions and downstream events. Methods: Human AD and control-brain extracts (ADbe and Ctrlbe) were infused in the hippocampus of Aβ plaque-bearing APPswe/PS1dE9 mice. We evaluated the links between Aβ plaques, tau aggregates, microgliosis, astrogliosis at the inoculation site and in connected regions (perirhinal/entorhinal cortex), and memory impairment and synaptic density 4 and 8 months post-inoculation. Results: ADbe-inoculated animals displayed memory deficit and synaptic loss in addition to Aβ and tau pathological aggregates. Aβ plaques were detected in both ADbe- and Ctrlbe-inoculated APPswe/PS1dE9 mice, but their load was increased close to the inoculation site in ADbe- inoculated animals. Tau-positive neuropil threads and neurofibrillary tangles occurred next to the inoculation site only in ADbe-inoculated animals and were not detected in Ctrlbe mice. These lesions spread to connected regions notably the perirhinal/entorhinal cortex. Tau-positive neuritic plaques were detected in both ADbe- and Ctrlbe-inoculated animals. Unexpectedly, ADbe inoculation did not increase the number of neuritic plaques close to the inoculation site as compared to Ctrlbe inoculation. ADbe inoculation however increased the area of tau-positive elements within these neuritic plaques. Increased tau pathology as well as lower Iba1-positive microglial load in the hippocampus and perirhinal/entorhinal cortex were correlated with memory impairment and with synaptic loss. Conclusions: The integrative analysis of pathological events associated with ADbe inoculation in Aβ-bearing mice highlighted memory and synaptic loss as well as the induction of tau lesions that spread in the brain. Increased tau lesions and lower microglial load are the two main events correlated with memory impairment and synaptic loss. The study suggests that microglial activity may be protective. Graphical abstract