Investigation of cortical circuits alterations in AD murine models: gustatory deficits and long-term effect of systemic inflammation

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition, neurofibrillary tangles, and neuroinflammation, which collectively contribute to disease progression. Early sensory deficits, such as olfactory impairments, have emerged as potential prodromal markers of AD, preceding the onset of overt cognitive decline. Alterations in taste detection, recognition, and preference have been reported in both AD patients and animal models, suggesting a link between gustatory processing and early neuropathological changes. Furthermore, growing evidence has identified inflammation as a key player in both the onset and progression of AD. Initially neuroprotective, promoting Aβ clearance and releasing trophic factors, neuroinflammation becomes chronic in advanced stages, creating a pro-inflammatory feedback loop that exacerbates neurodegeneration. Systemic inflammation, whether acute or chronic, has been shown to aggravate AD pathology by enhancing Aβ deposition, activating microglial Toll-like receptors (TLRs), and producing pro-inflammatory cytokines that compromise blood-brain barrier integrity and accelerate neuronal damage. To investigate the behavioral and neuronal correlates of AD at both early and late stages, we explored two different pathways: (i) gustatory processing and its potential alterations at the GC circuit level in APP/PS1 mice, and (ii) the long-term impact of systemic inflammation on medial prefrontal cortex (mPFC) neuronal activity in 3xTg-AD mice.