Transcriptional vulnerability to amyloid-β and tau pathologies differentially disrupts emotional and memory neural circuits

Alzheimer’s disease (AD) is characterized by memory loss and neuropsychiatric symptoms associated with cerebral accumulation of amyloid-β (Aβ) and tau, but how memory and emotional neural circuits are disrupted by AD pathology remains unclear. Here, we investigated the transcriptional vulnerability of memory and emotional circuits to concomitant Aβ and tau pathologies in transgenic mice expressing mutant human amyloid precursor protein (APP) and Tau (APP/Tau mice) in excitatory neurons. At 9 months, we detected common and region-specific transcriptional responses in the hippocampus and basolateral amygdala (BLA) of APP/Tau mice, including astrocytic, microglia and 63 AD-associated genes. These findings suggest that Aβ and tau pathologies disrupt region-specific gene expression programs underlying vulnerability of memory and emotional circuits to AD neuropathology. To study the effect of concomitant amyloid-β (Aβ) and tau neuropathology on memory- and emotion-processing circuits, 9-month-old double transgenic APP/Tau mice were trained in a cued fear conditioning/extinction paradigm, and the bulk transcriptomes of the basolateral amygdala (BLA) and hippocampus were analyzed.