Calcium Signaling May Be the Missing Link in Alzheimer’s Disease

Why Ca²⁺ dyshomeostasis may connect amyloid, tau, mitochondria, inflammation, and autophagy

Alzheimer’s disease (AD) is still not fully explained by any single mechanism. Classic hypotheses focus on amyloid-beta (Aβ) plaques and tau neurofibrillary tangles, while other frameworks emphasize mitochondrial dysfunction, chronic neuroinflammation, and impaired autophagy. This review argues that dysregulated calcium signaling, specifically Ca²⁺ dyshomeostasis, may be a central process that links these pathways into a more unified model. Ca²⁺ is a tightly controlled second messenger in neurons and glial cells, shaping neurotransmitter release, action potential signaling, synaptic plasticity, gene expression, and metabolic regulation. Under healthy conditions, extracellular Ca²⁺ can reach millimolar levels while intracellular Ca²⁺ remains near resting nanomolar ranges, only rising briefly and locally in specific microdomains during signaling. This control depends on coordinated Ca²⁺ entry and extrusion at the plasma membrane, storage and release from the endoplasmic reticulum (ER), buffering and uptake by mitochondria, and organelle-to-organelle contact sites such as mitochondria-associated membranes (MAM). In AD, injury-related factors can increase Ca²⁺ influx, weaken clearance, and drive persistent ER Ca²⁺ release, creating sustained Ca²⁺ overload in compartments where it becomes toxic rather than functional.

Ca²⁺ dyshomeostasis is proposed as a shared signaling hub connecting multiple AD hypotheses, including amyloid, tau, mitochondrial dysfunction, neuroinflammation, and impaired autophagy.

The review highlights that Ca²⁺ disruption may arise early and may not simply be a downstream consequence of plaques and tangles. Neuronal Ca²⁺ regulation is highly compartmentalized. Ca²⁺ enters via channels and transporters such as TRP channels, NMDAR, VGCC, CALHM, NCX, and PMCA. Small Ca²⁺ influx can activate phospholipase C signaling and generate IP3, which triggers Ca²⁺ release from ER stores through IP3R or ryanodine receptors (RyR). ER Ca²⁺ stores are replenished through store-operated calcium entry (SOCE), involving STIM sensing ER depletion, ORAI-mediated Ca²⁺ influx, and SERCA pumping Ca²⁺ back into the ER using ATP. Mitochondria act as Ca²⁺ buffers and sensors, taking up Ca²⁺ through VDAC and MCU, and exchanging ions through dedicated transport systems. The ER and mitochondria communicate through MAM, creating localized high-Ca²⁺ regions that can strongly shape metabolism and cell survival. When this network becomes dysregulated, neurons may shift toward hyperexcitability, synaptic instability, and degenerative cascades.

Fig. 1: Ca²⁺ homeostasis in neurons is maintained by membrane transport, ER storage and SOCE refilling, mitochondrial buffering, and ER-mitochondria exchange, but AD stress can tip this system toward sustained overload.

Within the amyloid cascade framework, APP processing shifts toward β-secretase pathways in AD, increasing production of Aβ peptides. These Aβ species can interact with Ca²⁺-related transport systems, including Ca²⁺-permeable AMPAR and other channels, driving excessive Ca²⁺ entry. In parallel, Ca²⁺ dysregulation can feed back into amyloid biology by influencing secretase-associated pathways and Ca²⁺-dependent signaling that promotes Aβ generation and plaque formation. The result is a reinforcing cycle: Aβ promotes Ca²⁺ influx, and Ca²⁺ imbalance increases amyloid burden, accelerating synaptic damage.

Fig. 2: Aβ-related processes and Ca²⁺ dysregulation can reinforce each other, promoting further amyloid production and worsening neuronal stress.

Ca²⁺ signaling is also deeply involved in tau pathology. Tau phosphorylation is regulated by multiple kinases, including PKA, PKC, CDK-5, CaMKII, GSK-3β, and MAPK, many of which are influenced by Ca²⁺-dependent cascades. The review emphasizes calpains, Ca²⁺-activated proteases, as key mediators. Calpain activity can enhance tau-kinase activity and promote tau hyperphosphorylation, and it may also cleave tau into fragments that more readily aggregate. At the same time, the authors note that these relationships can be complex and context-dependent, indicating that Ca²⁺-tau interactions may not follow a single linear pattern across all stages of disease.

Fig. 3: Caption suggestion: Elevated Ca²⁺ can drive kinase and calpain pathways that promote tau hyperphosphorylation, NFT formation, and aggregation-prone tau fragments.

Mitochondrial dysfunction is another major intersection. The brain’s energy demand makes neurons highly sensitive to mitochondrial impairment, and metabolic decline is an early and widespread feature in AD. Physiologically, moderate mitochondrial Ca²⁺ uptake supports ATP generation, but chronic mitochondrial Ca²⁺ overload lowers membrane potential (ΔΨm), disrupts oxidative phosphorylation, and promotes ROS accumulation. Sustained overload can drive irreversible opening of the mitochondrial permeability transition pore (mPTP), triggering apoptosis. The review also highlights MAM as a key structural site where ER-to-mitochondria Ca²⁺ transfer becomes intensified in AD, and where AD-associated proteins such as presenilins and APP fragments are enriched, suggesting a mechanistic link between Ca²⁺ transfer, mitochondrial stress, and amyloid-related pathology.

Fig. 4: Enhanced ER-to-mitochondria Ca²⁺ transfer through MAM can promote mitochondrial Ca²⁺ overload, impair respiration, increase ROS, and raise apoptotic vulnerability.

Neuroinflammation is likewise framed through a Ca²⁺ lens. Chronic activation of microglia and inflammasome pathways such as NLRP3 is a core feature of neuroinflammatory progression, and Ca²⁺ is a key signal in immune activation triggered by damage cues. Ca²⁺-dependent signaling such as PKC/MAPK/NF-κB supports pro-inflammatory microglial transitions, while channels such as CALHM2 can raise Ca²⁺ levels in disease-associated microglia and amplify inflammatory activity. Astrocytes also depend on Ca²⁺ signaling to regulate inflammatory behaviors and neuronal network effects. The review emphasizes that Ca²⁺ oscillations and Ca²⁺-dependent communication among microglia, astrocytes, and neurons may amplify inflammatory stress, and that enhanced Ca²⁺ signaling may weaken blood–brain barrier integrity, further aggravating AD pathology.

Fig. 5: Aberrant Ca²⁺ signaling can activate pro-inflammatory glia and amplify calcium-dependent inflammatory communication that damages neurons.

Autophagy dysfunction is presented as another Ca²⁺-linked mechanism. Autophagy depends on proper autophagosome formation, transport, fusion with lysosomes, and lysosomal degradation. Ca²⁺ signaling can regulate autophagosome initiation through TFEB-related pathways and Ca²⁺/CaMKII/AMPK/mTOR balancing. However, excessive Ca²⁺ signaling can suppress autophagy, and downstream calpain activity can cleave autophagy-related proteins such as ATG5, blocking autophagosome formation. Lysosomal acidification is another failure point: lysosomal Ca²⁺ homeostasis is intertwined with pH regulation, and excessive Ca²⁺ release can impair lysosomal acidification, reduce protease activity, and decrease clearance of damaged organelles and misfolded proteins, accelerating toxic accumulation.

Fig. 6: Dysregulated Ca²⁺ signaling can impair autophagy by inhibiting autophagosome formation and disrupting lysosomal Ca²⁺ balance and acidification, reducing clearance of toxic material.

Across these mechanisms, the review frames Ca²⁺ not as a single-direction “bad actor,” but as a concentration- and context-dependent regulator with dual effects. Excessive Ca²⁺ can promote Aβ generation, tau hyperphosphorylation, mitochondrial overload, oxidative stress, inflammatory activation, and autophagy suppression. Yet appropriately regulated Ca²⁺ signaling can support ATP production, autophagic flux, and adaptive cellular responses. This dual-faced nature suggests that therapeutic strategies should focus on restoring Ca²⁺ homeostasis with precision rather than globally suppressing Ca²⁺ signaling. The authors conclude that progress will depend on better in vivo tools, organelle-specific Ca²⁺ imaging, and improved disease models that directly capture Ca²⁺ dysregulation rather than relying solely on Aβ or tau overexpression.

Source
Wang M., Zhang H., Liang J., Huang J., Wu T., Chen N. (2025). Calcium signaling hypothesis: A non-negligible pathogenesis in Alzheimer’s disease. Journal of Advanced Research, 77, 513–534.