Beyond the brain: early autonomic dysfunction in Alzheimer's disease.

Area of Science:

• Neuroscience
• Endocrinology
• Pathophysiology

Background:

• Alzheimer's disease (AD) pathology is traditionally viewed as central, involving amyloid plaques and tau tangles.
• Emerging evidence suggests peripheral nervous system dysfunction, including the adrenal medulla, may contribute to AD.
• The adrenal medulla's role in AD pathogenesis remains under-investigated despite its function in stress response and neurotransmission.

Purpose of the Study:

• To investigate functional alterations in adrenal chromaffin cells (CCs) in a triple transgenic (3xTg) mouse model of AD.
• To assess the impact of these CC dysfunctions on systemic neurotransmitter levels and associated behaviors.

Main Methods:

• Electrophysiology to measure ion currents (Na+, Ca2+, K+, ACh) in 3xTg mouse CCs.
• High-resolution amperometry to assess vesicle release and fusion pore kinetics.
• Neurotransmitter quantification in plasma, brain, and other peripheral compartments; behavioral tests.

Main Results:

• Early (2-month-old) 3xTg CCs exhibit impaired exocytosis, reduced vesicle release, and slower fusion pore kinetics.
• Diminished Na+, Ca2+, and ACh currents compromise CC excitability, with age-related increases in K+ currents.
• Systemic neurotransmitter imbalances (altered noradrenaline, dopamine, serotonin) correlate with anxiety- and depression-like behaviors.

Conclusions:

• The adrenal medulla is an underrecognized site of early catecholaminergic dysregulation in Alzheimer's disease.
• Peripheral CC dysfunction contributes to systemic neurotransmitter imbalances and behavioral changes observed in AD models.
• These findings suggest a link between peripheral neuroendocrine alterations and central AD features, identifying the adrenal medulla as a potential therapeutic target and biomarker source.