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  3. Calcium dysregulation in Alzheimer's disease: unraveling the molecular nexus of neuronal dysfunction and therapeutic opportunities

Calcium dysregulation in Alzheimer's disease: unraveling the molecular nexus of neuronal dysfunction and therapeutic opportunities

  • Biochem Pharmacol. 2025 Dec;242(Pt 2):117211. doi: 10.1016/j.bcp.2025.117211.
Bharat Chaudhary 1,  Sneha Kumari 1,  Rishika Dhapola 1,  Prajjwal Sharma 1,  Mohit Paidlewar 1,  Balachandar Vellingiri 2,  Bikash Medhi 3,  Dibbanti HariKrishnaReddy 4
Affiliations

Affiliations

  • 1 Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, School of Health Sciences, Central University of Punjab, Ghudda, Bathinda 151 401 Punjab, India.
  • 2 Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab 151401 Bathinda, Punjab, India.
  • 3 Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
  • 4 Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, School of Health Sciences, Central University of Punjab, Ghudda, Bathinda 151 401 Punjab, India. Electronic address: harikrishna.reddy@cup.edu.in.
PMID: 40774399 DOI: 10.1016/j.bcp.2025.117211
Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by Aβ accumulation and tau hyperphosphorylation. Calcium dysregulation also plays a key role in its progression. As a vital second messenger, calcium ions regulate neuronal communication, memory formation, and learning, particularly in the hippocampus. Their levels are influenced by excitatory signaling, synapse formation, and neurotransmitter release. In AD, CA2+ dyshomeostasis occurs near amyloid plaques, marked by elevated intracellular calcium in neurons, microglia, and astrocytes, along with increased neuronal activity. Calcium dyshomeostasis promotes neurofibrillary tangle formation and amyloid-beta deposition through various molecular and signaling pathways. Elevated intracellular calcium accumulation results in multiple pathologies associated with AD, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, Apoptosis, and excitotoxicity through various calcium signaling pathways such as Calcineurin (CAN), calcium homeostasis modulator 2 (CALHM2), Mitogen-Activated Protein Kinase, Extracellular Signal-Regulated Kinase/ cAMP Response Element-Binding Protein (MAP/ERK/CREB), Wnt/β-catenin, Transient Receptor Potential Melastatin 2 (TRPM2), and Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) pathway. It is crucial to find the gap between calcium increase overloads and those associated with the neuropathology of AD. Several drugs target calcium signaling pathways and inhibit the disease progression in preclinical and clinical studies. The article highlights the significance of using therapeutic approaches specifically targeting calcium signalling pathways to enhance cognitive performance and decrease the progression of AD. Targeting calcium signalling holds promise for addressing the multifaceted pathologies of AD that will aid in combating the disease.

Keywords

Alzheimer’s disease; Calcium dysregulation; Glutamate excitotoxicity; Gut dysbiosis; Molecular pathways; Signalling pathways; Therapeutics.

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