Emerging insights into transient receptor potential channel-dependent calcium signaling dysfunction and neuronal vulnerability in Alzheimer’s disease

Alzheimer’s disease (AD) represents one of the most prevalent neurodegenerative disorders associated with aging and is marked by a gradual decline in memory, learning ability, and cognitive performance. While the accumulation of amyloid-β peptides and the formation of neurofibrillary tangles composed of hyperphosphorylated tau remain central hallmarks of the disease, growing evidence suggests that disruption of intracellular calcium ion (Ca 2+ ) homeostasis plays a fundamental role in initiating and accelerating neuronal damage. Sustained calcium imbalance interferes with synaptic signaling, disturbs neuronal excitability, impairs mitochondrial activity, and enhances oxidative as well as inflammatory stress within the brain microenvironment. Transient receptor potential (TRP) channels form a large and functionally diverse group of calcium-permeable ion channels that enable cells to respond to a wide range of physical and chemical stimuli. Within the nervous system, these channels participate in the regulation of neuronal excitability, synaptic plasticity, intracellular trafficking, autophagy, and glial cell activation. Alterations in TRP channel expression or activity have been linked to excessive Ca 2+ entry, defective clearance of misfolded proteins, and increased neuronal susceptibility to degenerative insults. Accumulating experimental studies indicate that TRP channels are actively involved in several key pathogenic mechanisms underlying AD. These include dysregulated lysosomal calcium signaling, mitochondrial calcium overload, abnormal amyloid precursor protein processing, tau hyperphosphorylation, and chronic neuroinflammation. Through these interconnected pathways, TRP channels appear to function as critical molecular nodes connecting calcium dyshomeostasis with progressive neurodegeneration. Importantly, modulation of specific TRP channel subtypes has demonstrated neuroprotective outcomes in both in vitro and in vivo AD models, underscoring their potential as therapeutic targets. This review provides a comprehensive overview of the molecular characteristics, physiological roles, and pathological alterations of TRP channels in AD. By integrating recent mechanistic findings, the article aims to enhance understanding of TRP-mediated calcium signaling in neurodegeneration and to outline future perspectives for the development of targeted therapeutic strategies.