Breaking Pathologic Neuroimmune Feedback Loops in Neurodegenerative Disorders

Alzheimer?s disease (AD), Parkinson?s disease (PD), and related neurodegenerative disorders represent major and escalating health challenges in aging populations, collectively affecting tens of millions of individuals worldwide. The World Health Organization projects that the global prevalence of dementia will reach 139 million people by 2050. Although AD and PD are clinically distinct, they share convergent pathogenic mechanisms, including chronic neuroinflammation, glial activation, blood-brain barrier dysfunction, and progressive neuronal vulnerability. Our preliminary work implicates the inducible kinin B1 receptor (B1R), upregulated under inflammatory conditions, as a critical regulator of neuroimmune signaling in the central nervous system. Here, we build on this evidence and propose the central hypothesis that aberrant activation of B1R and its endogenous agonists drives sustained neuroinflammation, thereby exacerbating neuropathology and functional decline in AD and PD. To test this novel model of disease pathogenesis, we will pursue these aims: Aim 1: Define the spatial and temporal distribution of B1R and its endogenous agonists in AD and PD. Aim 2: Assess the therapeutic efficacy of B1R targeting in AD and PD pathology. We will test whether selective pharmacologic antagonism of B1R signaling can rescue key disease phenotypes in AD and PD models.

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