Differential neural circuit vulnerability to β-amyloid and tau pathologies in novel Alzheimer’s disease mice

Abstract

AbstractAlzheimer’s disease (AD) progresses with memory loss and neuropsychiatric symptoms associated with cell specific vulnerability in memory- and emotion-related neural circuits. Neuropathological and synaptic changes are key factors influencing the clinical progression to dementia, but how they cooperate to cause memory and emotional disturbances is largely unknown. Here, we employed pathological, behavioral, expansion microscopy, electrophysiology and transcriptomic approaches to evaluate the effects of amyloid-β (Aβ) and tau on neuropathological progression, synaptic function, and memory and emotional symptoms in amyloid precursor protein (APP), Tau and double novel APP/Tau transgenic mice expressing the mutant human amyloid precursor protein (APPSw,Ind) and/or microtubule-associated protein tau (MAPT) in excitatory neurons. APP/Tau mice of both sexes show spatial learning and memory deficits associated with synaptic tau accumulation and reduced synaptic proteins and neurotransmission in the hippocampus. By contrast, male and female APP/Tau mice exhibit innate anxious behavior and impaired fear memory extinction linked to Aβ pathology and with absence of synaptic tau in the basolateral amygdala (BLA). Intriguingly, APP/Tau mice show NMDA-dependent long-term potentiation (LTP) deficits in the hippocampus but not in the amygdala. Bulk RNA sequencing reveals region-specific but also common transcriptional changes in response to Aβ/tau pathology, including downregulation of synapse transmission and ion channel activity genes. Importantly, we detected 65 orthologs of human AD risk genes identified in GWAS (e.g.,APOE,BIN1,CD33,CLU,PICALM,PLCG2,PTK2B,TREM2,SORL1,USP6NL) differentially expressed in the hippocampus and/or BLA of APP/Tau mice, indicating that this APP/Tau model exhibits transcriptional alterations linked to known molecular determinants of AD development. In conclusion, simultaneous development of Aβ and tau neuropathologies in this double APP/Tau transgenic mouse model reproduces synaptic, behavioral, and molecular alterations associated with AD pathophysiology in a region-specific manner. Our findings highlight region-specific pathological effects of Aβ and tau in excitatory neuronal circuits mediating emotional and memory processing, providing evidence that both factors and their molecular cascades should be considered in future AD preventive and therapeutic strategies.Graphical abstractAge-dependent vulnerability of memory and emotional neural circuits in response to tau and Aβ pathologies.