Re-examining Toll-Like Receptor Signaling in Alzheimer’s Disease: From Neuroinflammation to Circuit Alteration

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose mechanisms remain incompletely understood, and while amyloid and tau pathology have dominated the field, innate immune dysregulation has emerged as an increasingly important contributor to disease onset and progression. Toll-like receptors (TLRs), a family of pattern-recognition receptors that detect both pathogen-associated and damage-associated molecular patterns, have been implicated in AD risk and pathology through their roles in microglial responses to amyloid and tau aggregates, and through their activation by infectious agents, including herpesviruses, Chlamydia pneumoniae, and periodontal pathogens, that epidemiological evidence increasingly links to elevated dementia risk. Beyond their canonical immune functions, a growing body of evidence demonstrates that TLRs regulate synaptic plasticity, neuronal excitability, memory formation, adult neurogenesis, and dendritic morphology through mechanisms that are not reducible to classical neuroinflammation, suggesting that TLR dysregulation in AD may directly corrupt the cellular and circuit-level machinery. By re-examining specific AD studies through this expanded framework, this thesis argues that TLR2, TLR4, and TLR9 each act as mechanistic intermediates through which protein aggregation and glial activation are converted into synaptic failure, structural degeneration, and cognitive decline. This perspective carries practical implications for the design of vaccines and adeno-associated viral gene therapy vectors, both of which inadvertently engage TLR pathways in ways that may have underappreciated consequences for neuronal health in vulnerable aging populations, and it underscores the neurological urgency of more aggressive infection prevention and management strategies in individuals at risk for AD. Collectively, this thesis proposes TLR dysregulation in AD may affect the brain through mechanisms that are not reducible to neuroinflammation alone, and that incorporating their broader physiological roles into the conceptual framework of this neurodegenerative disease is essential for advancing both the mechanistic understanding and the clinical management of the disease.