Abstract
Non-cognitive behavioral and psychological symptoms often occur in Alzheimer's disease (AD) patients and mouse models, although the exact neuropathological mechanism remains elusive. Here, we report hyperactivity with significant inter-individual variability in 4-month-old APP/PS1 mice. Pathological analysis revealed that intraneuronal accumulation of amyloid-β (Aβ), c-Fos expression in glutamatergic neurons and activation of astrocytes were more evident in the frontal motor cortex of hyperactive APP/PS1 mice, compared to those with normal activity. Moreover, the hyperactive phenotype was associated with mislocalization of perivascular aquaporin 4 (AQP4) and glymphatic transport impairment. Deletion of the AQP4 gene increased hyperactivity, intraneuronal Aβ load and glutamatergic neuron activation, but did not influence working memory or anxiety-like behaviors of 4-month-old APP/PS1 mice. Together, these results demonstrate that AQP4 mislocalization or deficiency leads to increased intraneuronal Aβ load and neuronal hyperactivity in the motor cortex, which in turn causes locomotor over-activity during the early pathophysiology of APP/PS1 mice. Therefore, improving AQP4 mediated glymphatic clearance may offer a new strategy for early intervention of hyperactivity in the prodromal phase of AD.