Graduate Student Ottawa Hospital Research Institute Ottawa, Ontario, Canada
Abstract: Excessive eating behavior has been observed as a precognitive symptom prior to the onset of classical Alzheimer’s disease (AD) symptoms such as memory loss/cognitive decline. Currently, it is unknown how the abnormal food intake behavior directly links to AD pathophysiology. Interestingly, hyperphagia and perturbed neurogenesis have been reported in adult 3xTg-AD mice much earlier than the onset of AD pathological hallmarks. In addition, hypothalamic arcuate nucleus (ARC) satiety-activated proopiomelanocortin (POMC) neurons are reported to send long range axonal innervation to the ventral subdomain subventricular zone (vSVZ) and regulate vSVZ Nkx2.1 marked neural stem cell (NSC) activity in the rodent model. In this regard, it is important to determine the direct link between abnormal feeding behavior and perturbed neurogenesis in 3xTg-AD mice. Intriguingly, our food consumption study revealed drastic increases in the daily intake of food in the 3xTg-AD mice, and we found reduced ARC axonal inputs to contact Nkx2.1+ vNSCs in the 3xTg-AD mice via viral-mediated axonal tracing technique. Associated with this, we identified reduced activation rate of Nkx2.1+ quiescent NSCs (qNSCs) in the vSVZ of 3xTg-AD mice as well. Importantly, administering leptin, a neuropeptide involved in feeding regulation, for 7 days can successfully increase ARC POMC+ neuronal activity and specifically rescue deficits in the activation rate of vSVZ Nkx2.1+ qNSCs in 3xTg mice. Thus, the current study reveals that abnormal feeding behavior in 3xTg-AD mice is associated with perturbed ARC to SVZ neural circuits. This disrupted feeding circuit impairs regionally distinct SVZ Nkx2.1+ NSC activation, potentially contributing to reduced neuroregenerative plasticity/increased vulnerability in AD. Our study provides the basic understanding on how abnormal food intake behavior dampen neuronal vulnerability, contributing to AD pathogenesis before the onset of pathological hallmarks.
