Intraneuronal β-Amyloid Accumulation in the Amygdala Enhances Fear and Anxiety in Alzheimer's Disease Transgenic Mice

Background: Alzheimer's disease (AD) is characterized by progressive memory decline and neuropsychiatric symptoms. Despite common emotional symptoms in AD such as anxiety and fear are associated with a more rapid cognitive decline, the pathological mechanisms involved in these behavioral changes remain largely elusive. In this study, we examined the pathological mechanisms of emotional behavior in well-established AD transgenic mice expressing human mutant beta-amyloid (A beta) precursor protein (APP(Ind) and APP(Sw,Ind)) and tau (3xTg-AD). Methods: We evaluated unconditioned and conditioned fear-induced freezing behavior and spatial memory in APP(Ind), APP(Sw,Ind), and 3xTg-AD transgenic mice. The A beta and tau pathologies and signaling pathways involved in emotional processing were studied by immunohistochemistry and immunoblotting analyses. Results: The APP(Ind)/APP(Sw,Ind) and 3xTg-AD transgenic mice displayed at early ages enhanced innate and conditioned fear symptoms and spatial memory deficits coinciding with enhanced accumulation of A beta in gamma-aminobutyric acid (GABA)ergic and glutamatergic neurons, respectively, of the basolateral amygdala (BLA). Similarly, the number of neurons with intraneuronal A beta 40 and A beta 42 was significantly increased in the BLA of human AD brains. Fear responses might reflect an influence of anxiety, because the anxiolytic compounds valproate, diazepam, and buspirone reduced efficiently unconditioned and conditioned fear responses in APP transgenic mice. In addition, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, which is critical for acquisition and consolidation of fear conditioning, was increased in the amygdala of APP transgenic mice after cued conditioning. Conclusions: We propose a deleterious role of intraneuronal A beta on amygdala-dependent emotional responses by affecting the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway.