Prefrontal transcranial Direct Current Stimulation (tDCS) restores dopaminergic function and mitigates Alzheimer’s Disease-like deficits in Tg2576 mice

Emerging evidence implicates early dysfunction of dopaminergic neurons in the Ventral Tegmental Area (VTA) as a key contributor to Alzheimer’s disease (AD) pathophysiology. This study evaluated the therapeutic potential of repeated prefrontal transcranial Direct Current Stimulation (tDCS) in the Tg2576 mouse model of AD, characterized by early VTA dopaminergic neurodegeneration. Repeated tDCS was applied to assess its effects on VTA dopaminergic activity, dopamine (DA) release, synaptic plasticity, behavior, neuroinflammation, and AD-related pathology. Hippocampal DA release, Nucleus Accumbens (NAc) dopamine transporter (DAT) expression, microglial alterations, intracellular amyloid-β (Aβ) levels, and plaque burden were evaluated. Prefrontal tDCS enhanced VTA dopaminergic neuron activity, increasing hippocampal DA release and DAT expression in the NAc. These effects were associated with restored CA3–CA1 synaptic plasticity and improved recognition memory and motivational behaviors. tDCS also reduced microglial density and morphological complexity at both pre-plaque (7 months) and advanced (12 months) disease stages. Furthermore, tDCS decreased Aβ plaque burden, although intracellular Aβ levels remained unchanged in younger Tg2576 mice. Overall, these findings highlight the multifaceted therapeutic potential of prefrontal tDCS in AD by targeting dopaminergic dysfunction, synaptic impairments, neuroinflammation, and amyloid pathology. As a non-invasive neuromodulatory approach, tDCS may represent a promising early intervention strategy to complement existing AD treatments.