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

INTRODUCTION

Alzheimer’s disease (AD) is a progressive disease like dementia that causes a gradual and total loss of cognitive function, ultimately leading to early death.^[1] The inability of neurons to maintain proper intracellular calcium (Ca²⁺) levels is a key component of the neurodegenerative process of the disease.^[2] Disturbances of calcium homeostasis are essential for the development of AD because they lead to neuronal injury and synaptic dysfunction, and the accumulation of harmful protein aggregates including tau tangles and amyloid plaques.^[3] These cellular abnormalities dysregulate brain regions related to memory and cognition and accelerate cognitive decline.^[4] In addition, high levels of amyloid-beta (Aβ) peptide cause the production of pro-inflammatory cytokines and toxic reactive oxygen species (ROS) that further impair Ca²⁺ control and make neurons more vulnerable to excitotoxicity and death.^[5] The development and progression of AD are also greatly impacted by transient receptor potential (TRP) channels, an extensive category of ion channels linked to Ca²⁺ signaling. TRP channel disruption can lead to high Ca²⁺ influx and neuronal injury by disrupting Ca²⁺ homeostasis.^[6] For instance, more oxidative stress and inflammation are connected with overactivation of TRP melastatin (TRPM)-2 and TRP vanilloid (TRPV)-1 channels that complicates neurodegeneration.^[7] It is important to note that while increases in intracellular calcium levels can be toxic, the toxicity of this increase depends on the particular Ca²⁺ channel that facilitates Ca²⁺ influx.^[8] For example, Ca²⁺ influx through N-methyl-d-aspartate receptor can cause cell damage, although comparable increases through other channels such as Alpha- Amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or KCl therapy may not be harmful.^[9] These results demonstrate how calcium signaling in AD is complex and contradictory, with different contexts of Ca²⁺ regulation potentially having both protective and detrimental effects on neurons.

The TRP family of ion channels, first identified in Drosophila, plays a critical role in regulating calcium levels in cells, which affects many physiological functions, including sensory perception, cell signaling, and neuronal activity.^[10] The TRP canonical (TRPC) family has several subfamilies, such as TRPC, TRPM, and TRPV. TRPC channels, such as TRPC1 and TRPC3, and store-operated calcium entry (SOCE), which help maintain calcium homeostasis in neurons.^[11] TRPC channels, such as TRPM2 and TRPM7, are activated by oxidative stress and contribute to cell survival or death under stressful conditions, playing a role in neurodegenerative diseases and other pathologies.^[5] TRPV channels, including TRPV1, are responsible for sensing pain, temperature, and other physical stimuli; TRPV1 specifically recognizes heat and capsaicin and enhances the feeling of inflammation and pain.^[12] Many TRP channels, in addition to functioning in ion transport, are localized in a specialized membrane domain called lipid rafts. These processes help control Aβ production and signaling proteins, indicating their involvement in neurodegenerative diseases such as AD.^[13] Overall, TRP channels are important in normal cellular functions, and disruption of their activity can lead to a number of diseases, making them important targets in therapeutic research. Function of TRP channel in AD TRP channels damages brain cells in AD, leading to cognitive impairment that is characteristic of the disease.^[14] These channels regulate the movement of Ca²⁺ and other ions inside and outside of the neurons, which are essential for learning, memory formation, and other normal brain functions.^[15] However, AD throws off this tight balance. Abundant Ca²⁺ leads to overactive TRPC, TRPM, and TRPV family channels.^[7] This overload weakens neurons and makes them more susceptible to damage, causing oxidative stress and mitochondrial damage to cells.^[5] Tau, a protein that keeps neurons structurally healthy, is one of the most dangerous effects of too much Ca²⁺. When Ca²⁺ levels rise, tau becomes hyperphosphorylated, which causes neuronal tangles.^[16] These tangles of neurofibrillary interfere with brain activity and result in disorientation and memory loss. Moreover, stress can raise the risk of TRPC, TRPM, and memory loss. Activates TRPM2 and TRPM7 channels, especially when there are Aβ plaques.^[17]

Increased Ca²⁺ overload is another hallmark of AD, feeding a vicious cycle that accelerates mental impairment and neuronal damage. TRPV1 channels, which sense pain and heat, can also exacerbate Ca²⁺ deficiency and the inflammation typical of AD. Inflammation accelerates cognitive decline and damages neurons.^[18] Understanding the role of these TRP channels in the disease process offers new therapy options. The aim of research on these channels is to inhibit the growth of AD, reduce ROS, and restore calcium homeostasis. TRP channels are important for disease pathophysiology and normal brain function [Figure 1].

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Figure 1: Diagram illustrating the involvement of transient receptor potential (TRP) channels in Alzheimer’s disease-related neurodegeneration. Amyloid-beta oligomers stimulate TRP channels such as TRP melastatin (TRPM)-2 and TRPM7, resulting in excessive entry of calcium ions into neurons. This calcium imbalance disrupts mitochondrial function and promotes the formation of reactive oxygen species, leading to oxidative stress and abnormal tau phosphorylation. Activated microglial cells release inflammatory cytokines including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and Interleukin-6 (IL-6), which further intensify neuroinflammatory responses. Together, calcium dysregulation, oxidative damage, and inflammation contribute to synaptic dysfunction and progressive neuronal degeneration. ROS: Reactive oxygen species

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INFLUENCE OF TRP CHANNELS ON LEARNING, MEMORY, AND COGNITIVE DETERIORATION

Association between key pathological features of AD and impaired Ca²⁺ regulation

A growing body of research indicates that alterations in intracellular Ca²⁺ regulation play a fundamental role in the development and progression of AD.^[28] Disturbed Ca²⁺ signaling has been increasingly linked to several defining pathological features of the disease. Among the cellular compartments affected, lysosomes have gained particular attention due to their central role in protein turnover and amyloid metabolism. Impairment of lysosomal function strongly contributes to the accumulation of toxic Aβ species, ultimately promoting neuronal dysfunction and degeneration.^[29] Normal lysosomal activity relies on the preservation of an acidic internal environment, which is essential for efficient degradation of misfolded and aggregated proteins. This acidic balance is maintained through coordinated proton and calcium transport mechanisms. Proton influx into lysosomes is primarily mediated by vacuolar-type H⁺-ATPase (V-ATPase), whereas alkalinizing processes involve Ca²⁺-dependent pathways, including Ca²⁺/ H+ exchange through the Ca²⁺/H⁺ exchanger (CAX) and Ca²⁺ release through ion channels such as TRP mucolipin (TRPML) and two-pore channels.^[8,30] Under physiological conditions, these mechanisms operate in equilibrium, allowing lysosomes to maintain optimal pH and proteolytic efficiency. In AD, however, this finely regulated balance becomes disrupted. Enhanced CAX activity promotes excessive proton efflux in exchange for Ca²⁺ entry, leading to progressive lysosomal alkalization.^[31] Because an acidic environment is critical for autophagosome lysosome fusion and enzymatic protein breakdown, alkalization markedly compromises autophagic flux. As a result, impaired lysosomal clearance facilitates the intracellular accumulation of Aβ oligomers, which contributes to synaptic dysfunction and neuronal toxicity.^[32]

Lysosomal Ca²⁺ signaling also plays a key role in regulating autophagy during cellular stress conditions. In response to elevated oxidative stress, a prominent feature of AD pathology Ca²⁺ is released from lysosomes mainly through TRPML1.^[29] This Ca²⁺ signal activates the phosphatase calcineurin, which subsequently dephosphorylates transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy-related gene expression. Once dephosphorylated, TFEB translocates to the nucleus and stimulates transcriptional programs that support cellular clearance mechanisms.^[31] Persistent disruption of this regulatory pathway in AD weakens these adaptive responses, further aggravating defects in proteostasis. Disturbed Ca²⁺ homeostasis is also closely linked to tau pathology, another major hallmark of AD. Several enzymes responsible for tau phosphorylation are Ca²⁺ dependent. Elevated intracellular Ca²⁺ levels activate calpain proteases, which cleave the regulatory protein p35 to generate the more stable fragment p25. This conversion leads to sustained activation of cyclin-dependent kinase 5 (CDK5), resulting in abnormal tau hyperphosphorylation.^[33]

Accumulation of hyperphosphorylated tau destabilizes microtubules, disrupts axonal transport, and promotes the formation of neurofibrillary tangles, thereby accelerating neuronal degeneration. In addition to lysosomal dysfunction, Ca²⁺ imbalance profoundly affects mitochondrial homeostasis in AD.^[34] Mutations in presenilin proteins enhance Ca²⁺ release from the endoplasmic reticulum (ER), increasing Ca²⁺ transfer to mitochondria through voltage-dependent anion channels and the mitochondrial calcium uniporter.^[35] Excessive mitochondrial Ca²⁺ accumulation disrupts oxidative phosphorylation and stimulates overproduction of ROS, which promotes opening of the mitochondrial permeability transition pore (mPTP).^[36] ROS further exacerbate Ca²⁺ dysregulation by activating ryanodine receptors, thereby increasing Ca²⁺ release from the ER and reinforcing a self-perpetuating cycle of oxidative stress and calcium overload. Sustained mitochondrial Ca²⁺ elevation triggers cytochrome c release and activation of intrinsic apoptotic signaling pathways, ultimately leading to neuronal loss.^[13] Moreover, Aβ peptides interact with cyclophilin D, facilitating mPTP opening and further increasing mitochondrial vulnerability, thereby strengthening the link between amyloid pathology and Ca²⁺-mediated neurodegeneration.^[37] Taken together, these observations indicate that disrupted Ca²⁺ homeostasis represents a central pathological axis integrating lysosomal dysfunction, impaired autophagy, tau hyperphosphorylation, mitochondrial failure, and oxidative stress in AD.^[29] The involvement of TRP channels at multiple regulatory checkpoints places them at a critical intersection of intracellular Ca²⁺ signaling pathways, highlighting their importance in AD pathogenesis and their potential relevance as therapeutic targets [Figures 2-4].

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Figure 2: Schematic representation showing the role of transient receptor potential ankyrin (TRPA)-1 channels in neuronal death during Alzheimer’s disease. Neuroinflammation induces sustained calcium ion (Ca²⁺) influx through TRPA1, leading to mitochondrial dysfunction, caspase-3 activation, reactive oxygen species generation, and apoptotic neuronal loss. In microglia, Ca²⁺-dependent activation of Protein phosphatase 2B (Capcineurin) (PP2B) stimulates calpain-1, NF-κB: nuclear factor kappa B, and Nuclear factor of activated T-cells (NFAT) signaling, promoting amyloid-β production and release of pro-inflammatory mediators. Increased oxidative stress further disrupts cholinergic signaling by enhancing acetylcholinesterase activity, ultimately contributing to cognitive decline. Inhibition of TRPA1 may provide neuroprotective effects in Alzheimer’s disease. ROS: Reactive oxygen species, IL-1: Interleukin-1, amyloid precursor protein (APP), Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1).

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Figure 3: Schematic illustration depicting the neuroprotective role of the transient receptor potential canonical (TRPC)-6 channel in Alzheimer’s disease-associated neuronal death. Activation of TRPC6 by positive modulators such as hyperforin promotes calcium ion (Ca²⁺) entry, leading to the activation of Calcium/ calmodulin dependent protein kinase II (CaMKII). Activated CaMKII triggers two major signaling routes: (a) direct phosphorylation of Camp response element binding protein (CREB) to its active form (p-CREB) and stimulation of the Mitogen activated protein kinase (MAPK) pathway, which further enhances CREB phosphorylation. Elevated p-CREB mediates neuroprotection through multiple mechanisms, including suppression of N-methyl-d-aspartate receptor-dependent Ca²⁺ overload that contributes to excitotoxicity, oxidative stress, and mitochondrial dysfunction. In addition, CREB signaling inhibits amyloid precursor protein processing by β- and γ-secretases, thereby reducing the formation of toxic amyloid-β oligomers and plaques. Increased CREB activity also supports mitochondrial stability and promotes synaptogenesis, improving synaptic plasticity and protecting hippocampal neurons from degeneration. TRPC6: Transient receptor potential canonical 6, APP: Amyloid precursor protein (APP),BACE1: Beta-site amyloid precursor protein cleaving enzyme 1, NMDA: N-Methyl-D-Aspartate, ATP: Adenosine triphosphate.

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Figure 4: Schematic illustration showing the pathogenic involvement of the TRP melastatin (TRPM)-2 channel in neuronal death associated with Alzheimer’s disease. Amyloid-β (Aβ) plaques initiate neurotoxicity by inducing excessive reactive oxygen species (ROS) generation and subsequent activation of TRPM2 channels. Elevated ROS promotes the formation of ADP-ribose (ADPR) from NAD⁺ through the actions of poly(adp-ribose) polymerase 1 (PARP-1) and PARG. While PARP-1 contributes to pathological microglial activation, ADPR functions as a key modulator of TRPM2, facilitating Aβ-dependent channel opening and calcium ion influx. Concurrently, Aβ-stimulated microglia release pro-inflammatory cytokines, including interleukin-1β and tumor necrosis factor-α (TNF-α), which further amplify oxidative stress and activate caspase-mediated apoptotic pathways. Depletion of the glutathione antioxidant defense system fails to neutralize excessive ROS, ultimately resulting in progressive neuronal death glutathione (GSH), reactive nitrogen species (RNS) Interleukin-1β, nicotinamide adenine dinucleotide (NAD) , Protein Kinase C (PKC). Mitogen-Activated protein kinase / Extracellular signal-regulated kinase (MEK/ERK),NADPH Oxidase (NOX).

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STRUCTURE AND COMPONENTS OF TRP CHANNELS

TRP CHANNEL REGULATION

TRP channels are multifunctional and versatile and are important in sensing and responding to physical and environmental stimuli. These channels can be turned on for thermosensation, pain perception, mechanotransduction, and cellular signaling.^[50] Ligand binding is an important activation mechanism, with responses to chemical agonists coming from specific TRP channels; TRP ankyrin (TRPA)-1, for example, is activated by acidic pH and capsaicin (the active ingredient in chili peppers), TRPA8 responds to menthol and cold temperatures, while TRPA1 is activated by stimulants such as oxidative stress molecules and mustard oil.^[51] Another trait of TRP channels is temperature sensitivity. TRPM8 detects cold temperatures, but TRPV1 and TRPV2 detect excessive and noxious heat.^[12] Voltage sensitivity is also important, especially in the TRPM4 and TRPM5 channels, which are modulated by changes in membrane potential.^[52] The mechanosensitive channels TRPV4, TRPP1, and TRPP2 function to respond to physical forces and maintain homeostasis of the nervous system.^[53] TRP channels serve as sensitive receptors in the brain that respond to a range of stimulation such as temperature, oxidative stress, mechanical pressures, chemical signals, and pH variances, keeping equilibrium and neural transmission.^[49,54] TRPC1 is crucial for SOCE modulating calcium signaling by monitoring calcium depletion in the ER. Oxidative stress stimulates TRPA1 and TRPM2, ultimately leading to inflammation and the death of neurons.^[7,46] TRPV1 and TRPC6 are affected by phospholipids that contain phosphatidylinositol 4,5-bisphosphate and second messengers including diacylglycerol and inositol triphosphate, which influence how TRPC1 combines with stromal interaction molecule 1 for calcium regulation with acidic conditions triggering TRPV1 and TRPM7, TRP channel power to detect pH changes equally significantly and raises their functional activities.^[55]

TRP channels are found across important brain areas including the Substantia nigra, amygdala, cortex, hippocampus, and cerebellum.^[56] They serve a range of functions in memory, sensory perception, and neuronal defense. TRPV1 senses heat and capsaicin, the substance that gives chili peppers their spicy flavor, whereas TRPM2 and TRPM7 promote immunological response and neuronal survival by preventing oxidative stress.^[45,57] When TRPA2 affects pathways related to inflammation and pain, TRPA1 controls calcium signaling and neuronal protection.^[58] Nevertheless, abnormal TRP channels are linked to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and AD with TRPA7 and TRPA5 having essential for the degeneration of motor neurons. TRPC4 and TRPC5 are additionally connected to anxiety and depression because they alter stress responses and emotional regulation.^[59] Because of their intricacy and versatility, TRP channels serve as an essential for sensory input, neural defense, and stress tolerance, but if they are dysregulated, it may lead to inflammation, oxidative stress, and neuronal damage, which can exacerbate migraines, chronic pain, and neurodegenerative disease.^[60] Nevertheless these difficulties, TRP channels provide promising targets for treatment. Knowing their mechanism and role is opening the door to therapies that fight neurological disease, reduce inflammation and chronic pain.^[61] Research creates progress in solving some of the most difficult nervous system problems and promoting brain health by researching the mechanism of TRP channel.

ROLE OF TRP CHANNEL IN SYNAPTIC PLASTICITY IN AD

The ability of the brain to change the strength of connections between neurons in response to learning and memory is referred to as synaptic plasticity, and TRP channels serve as essential regulators of this process.^[68] In AD, cognitive decline leads to a widespread impairment in this mechanism. Ca²⁺ levels, which are modulated by TRP channels, are essential for neurotransmitter release, neuronal survival, and synaptic transmission.^[69] TRPC1 and TRPC5 maintain the equilibrium between excitatory and inhibitory impulses in a healthy brain, while TRPC6 improves memory formation by enhancing synapses.^[70] However, in AD, oxidative stress and Aβ plaques overactivate TRPV1, TRPA1, and TRPM2, leading to a loss of Ca²⁺ levels. Ca²⁺ influx, neuronal excitability, and synapse loss increase.^[71] This imbalance triggers LTD which destroys memory pathways and inhibits LTP, the process that builds neuronal connections for learning.^[72] Besides damaging neurons and accelerating cognitive impairment, TRP channel failure also increases glutamate release. Furthermore, neuronal death leads to oxidative stress, inflammation, and mitochondrial damage that begins with overactive TRPM7 and TRPV4 channels.^[73] TRP channels are being recognized as important therapeutic targets for AD due to their direct association with memory loss and neurodegeneration.^[74] While suppressing TRPM1 and TRPM2 can reduce neuronal damage by preventing excessive calcium accumulation and oxidative stress, blocking TRPV4 channels has been shown to be beneficial in preventing neuronal damage.^[75] Restoring TRPC6 activity may help recover from synaptic loss and enhance cognition.^[76] Future medications for treating memory loss and cognitive decline show promise as scientists are investigating novel ways to maintain neurons, restore synaptic plasticity, and slow the development of AD by understanding how TRP channels interact with the disease.

ROLE OF TRP CHANNEL IN Aβ AND TAU PATHOLOGY

The pathological mechanism of Aβ in AD is strongly impacted by TRP channel that leads to synapse loss, neuronal malfunction, and cognitive decline.^[77] These channels control Ca²⁺ homeostasis, which is essential to maintain proper neural communication.^[78] However, in AD, the disruption leads to high Ca²⁺ influx, oxidative stress, mitochondrial damage, and neuroinflammation, various factors that increase the disease.^[79] When TRPV1, TRPM2, and TRPC6 are overactivated, Aβ synthesis and deposition rise, which stimulate the formation of toxic plaques that inhibit synaptic transmission through the activation of kinases such as glycogen synthase kinase 3 beta and CDK5. TRPM7 and TRPV4 also contribute to tau pathology by hyperphosphorylating tau and generating neurofibrillary tangles that interfere with neuronal transport and disrupt the cytoskeleton.^[44] An outcome neurons gradually decline, especially in sections such as cortex and hippocampus that are connected to memory. In addition, TRP channel failure contributes to neuroinflammation by triggering microglial and astrocytic activation and generating pro-inflammatory cytokines that enhance neuroinflammation and encourage tau and Aβ pathology.^[80] On the other hand, downregulation of TRPC6, which is typically profitable and promotes synaptic plasticity, impairs the brain’s natural defense against Aβ and tau toxicity in AD.^[81] Because of their essential function in the pathogenesis of AD, TRP channels became known as possible therapeutic targets.^[11] By decreasing oxidative stress, neuroinflammation, and Ca²⁺ overload, overactive TRPV1 and TRPM2 regulation may reduce tau hyperphosphorylation and Aβ production. Memory and synaptic integrity can also be preserved by recovering TRPC6 activity.^[59] A deeper understanding of the intricate role that TRP channels play in Aβ and tau pathology supports the development of treatments that maintain cognitive function while decreasing the progression of AD.

TRP CHANNELS AS THERAPEUTIC TARGETS IN ALZHEIMER’S DISEASE

A challenging and disruptive disorder, AD is caused by many kinds of destructive events, such as calcium imbalance, chronic inflammation, glial cell failure, and the buildup of toxic proteins that include tau and Aβ.^[77] The vital role that TRP channels play in these processes has been discovered in a recent study, so they make them attractive potential for prospective therapies intended to prevent the progression of AD and preserve brain function.^[44,56]

Calcium regulation is one of the early disturbances in AD, which pushes neurons and causes cell death. TRP channels, particularly TRPM2 and TRPC6, are important for maintaining calcium levels.^[82] It has been demonstrated that increasing TRPC6 activity facilitates synaptic plasticity and memory but overactive TRPM2 triggers oxidative stress and neuronal death. TRPV1 and TRPA1 are examples of hyperactive TRP channels that increase chronic inflammation by stimulating the synthesis of inflammatory chemicals which is another hallmark of AD.^[28,82] Through blocking these channels, neuroinflammation can be reduced and cognitive decline can be slowed.^[82]

Glial cells, astrocytes, and microglia are essential for brain health in addition to neurons due to their assist in balance and the elimination of toxic substances.^[83] But in AD, these sustaining cells can grow toxic due to the dysfunction of TRP channels such as TRPV4 and TRPM7, which result to nerve cell damage opposed to preventing it. By restoring these channels’ protective role, neurotoxicity might be reduced, and brain resilience increased.^[84]

Aβ plaques and tau tangles which interfere with brain function and promote neurodegeneration are characteristics of AD. Some TRP channels such as TRPM2 and TRPV1 promote the dangerous buildup of Aβ, but other channels such as TRPC1 and TRPC3 have been linked to its clearance.^[85] Neurofibrillary tangles that lead to further damage can also result from tau hyperphosphorylation which is triggered by oxidative stress and calcium excessive amount. Researcher needs to reduce the excessive tau formation that causes cognitive decline by altering TRPM7 and TRPV1.^[86] Toxic protein build-up can be avoided, inflammation can be reduced, glial function can be improved, and calcium homeostasis can be restored by targeting TRP channels. With the potential to delay the progress of the illness and enhance cognitive function, these channels give a hopeful novel approach for treating AD, even if research is still in its early stages.^[87] To develop effective treatments for one of the most severe neurological diseases of our day, we may need to better understand and use TRP channels.

CHALLENGES OF TARGETING TRP CHANNELS IN AD

Preventing AD by attacking TRP channels is promising, but there are many challenges that must be investigated. One main concern is that TRP channels in the brain can have beneficial as well as harmful effects, such as TRPC6 protecting memory and brain function and damaging other nerve cells, including TRPM2 and TRPV1.^[47] It is extremely challenging to develop a drug that can safely modulate their function without causing unexpected negative consequences. One of the primary challenges is the calcium imbalance that is an essential component of AD.^[88] TRP channels help control calcium levels in nerve cells, but when they become overactive, particularly TRPM2 and TRPC5, they flood the cells with too much calcium. This overload can lead to nerve cell damage, energy failure, and harmful tau build-up, which worsens memory loss.^[89] However, completely blocking these channels is also not a solution, as calcium is essential for learning and communication between brain cells. Finding the right balance is a major challenge. Inflammation in the brain adds another layer of complexity. TRP channels, such as TRPV1 and TRPA1, help the brain’s immune cells (such as microglia and astrocytes) control how they respond to Aβ plaques, one of the main culprits of AD.^[90] Blocking these channels can reduce harmful inflammation, but it can also prevent the brain from clearing Aβ plaques, making the disease worse. Another problem is that there are very few drugs that specifically target TRP channels without affecting other ion channels or biological processes. Many existing drugs come with unwanted side effects. In addition, the blood–brain barrier makes it difficult for potential treatments to reach the right areas of the brain in sufficient quantities.^[91] Finally, findings from laboratory and animal studies often fail to translate into successful outcomes in human clinical trials. The way TRP channels work in mice or rats is not always the same as in humans, making it difficult to predict how well a drug will work in real patients.^[92] AD is an extremely complex disease, involving multiple biological pathways, so targeting TRP channels alone may not be enough or may require a combination of treatments to make a real difference.^[93] TRP channels remain a focus for future AD treatment with all of these challenges. Researchers are working on more exact medication, better way to track TRP channel activity, and patient-specific therapies. With continued research, TRP-based therapies could eventually help in the prevention or slowing of AD.

RESEARCH GAPS AND FUTURE PERSPECTIVES

Although considerable progress has been made in elucidating the role of TRP channels in AD, multiple conceptual, experimental, and translational gaps remain. Addressing these limitations is essential for advancing TRP channel-based therapeutic strategies and improving our understanding of calcium-mediated neurodegeneration.

CONCLUSION

AD develops through the combined action of several pathological processes that gradually weaken neuronal structure and impair cognitive ability. Among these changes, disturbance of intracellular Ca²⁺ regulation has gained increasing importance, as it directly affects synaptic communication, cellular metabolism, and neuronal survival. Because TRP channels are widely distributed throughout the brain and respond to multiple forms of cellular stress, they play a significant role in shaping calcium-dependent signaling during disease progression.

Studies discussed in this review indicate that TRP channels contribute to different phases of Alzheimer’s pathology. Excessive or prolonged activation of certain calcium-permeable TRP channels can lead to abnormal calcium entry, triggering oxidative stress, mitochondrial dysfunction, lysosomal impairment, and persistent inflammatory responses in neurons and glial cells. In contrast, some TRP channel subtypes appear to support synaptic function and help maintain cellular stability, highlighting the functional complexity of this channel family.

Although growing evidence supports the involvement of TRP channels in AD, their precise roles remain incompletely understood. Variations in channel expression among brain regions, differences between neuronal and glial populations, and dynamic changes across disease stages complicate interpretation. Importantly, current findings suggest that generalized suppression of calcium signaling is unlikely to be beneficial and may even worsen neuronal damage. These observations underline the need for carefully targeted approaches aimed at specific TRP channel subtypes to achieve effective and safe therapeutic outcomes.