NORADRENERGIC DENERVATION AS A POSSIBLE DRIVER OF MULTIPLE SYSTEM DEGENERATION AND BLOOD–BRAIN BARRIER DISRUPTION IN AGING

The locus coeruleus (LC) is the primary source of noradrenaline in the brain and plays a critical role in neuromodulation, vascular regulation, and maintenance of brain integrity during aging. Degeneration of LC noradrenergic neurons is an early and consistent feature of Alzheimer’s and Parkinson’s disease; however, its long-term impact on interconnected neural and vascular systems remains poorly understood. Emerging evidence suggests that noradrenergic loss may increase the vulnerability of dopaminergic and cholinergic neurons and compromise blood–brain barrier (BBB) integrity.
In this study, we used the DSP4 rat model of noradrenergic degeneration to examine whether chronic LC degeneration drives progressive multiple system pathology during aging. Animals received DSP4 (50 mg/kg) and were aged to 18 months, with a booster dose administered at 9 months. Brain tissue was collected and is currently being processed for immunohistochemical analyses using tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), SMI-71, glial fibrillary acidic protein (GFAP), and NeuN to assess noradrenergic, cholinergic, vascular, glial, and neuronal integrity, respectively.
Anxiety-like behavior was assessed longitudinally using the zero-maze test, revealing increased anxiety-like behavior in DSP4-treated animals compared with controls. Blood samples were collected every three months, and serum S100B levels were measured as a peripheral marker of BBB integrity. Unexpectedly, significantly higher S100B levels were observed in control animals at the 15-month time point.
These findings provide insight into LC-dependent neuromodulatory mechanisms contributing to brain vulnerability and resilience during aging.