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Advanced Neurology TRPM2 in neurological disorders

a TRPM2 inhibitor, which decrease apoptosis and Ca To study tau pathology, transgenic mice were developed
2+
influx . In SH-SY5Y cells overexpressing TRPM2, cell that express human tau through different promoters .
[5]
[47]
viability was reduced relative to wild-type cells in response When the P301L mutation is present in the human
to H O exposure, which was prevented by TRPM2 and microtubule-associated protein tau gene, which encodes
2
2
PARP inhibition . Overall, MPP increases TRPM2 tau protein, mice homozygous for this transgene develop
+
[48]
expression in SH-SY5Y neurons, increasing caspase neurofibrillary tangles by 4.5 months and experience
activation, and reducing cell viability [48-50] . neuronal loss, particularly in the spinal cord . To develop
[55]
Results from human, animal, and in vitro studies are mouse models that encompass both plaques and tangles,
complementary. Sun et al. showed that TRPM2 levels are transgenic tau and APP mice have been crossed. These
increased in the substantia nigra in both an MPTP-induced mice develop Aβ pathology as per the transgenic APP
mouse model and human PD patients . ROS-mediated model, with enhanced neurofibrillary tangle pathology in
[38]
TRPM2 activation also induced cell death or apoptosis in the olfactory cortex and limbic system relative to single
SH-SY5Y cells through elevation of Ca 2+[38] . transgenic tau mice [56,57] , indicating that Aβ exacerbates
tau pathology .
[57]
These findings in PD animal models, cell cultures, and
humans indicate a role for TRPM2 in neuronal dysfunction Mechanisms of TRPM2 action on AD progression
through ROS-mediated activation of TRPM2 and loss of have been detailed in cell culture and animal studies.
intracellular Ca homeostasis, leading to apoptosis. In hippocampal neurons extracted from mouse brain
2+
tissue and exposed to Aβ, ROS were generated through
3.2. AD protein kinase C and nicotinamide adenine dinucleotide
[58]
Similar to PD, oxidative stress contributes to AD development. phosphate (NADPH)-dependent oxidases . In cultured
ROS may be generated through mitochondrial dysfunction rat striatal cells exposed to Aβ and H O , blocking TRPM2
2
2
and autophagy , activation of microglia , and amyloid-β function (through transfection with a splice variant) or
[51]
[51]
(Aβ) (1 – 42) through binding iron . downregulating its expression (through siRNA) prevented
[51]
intracellular increases in Ca and resultant cell death .
2+
[59]
According to the amyloid hypothesis, there is an In addition to calcium overload, increases in cytosolic
overproduction of amyloid precursor protein (APP), or and mitochondrial Zn may also induce apoptosis.
2+
problems in clearing APP, leading to increased amyloid The increase in cytosolic Zn occurs through TRPM2-
2+
concentration in tissue . Drugs developed to target amyloid mediated Ca increases that lead to the release of Zn
[1]
2+
2+
have generally been unsuccessful when translated from by lysosomes . Mitochondria are affected by lysosome-
[60]
mice to humans. This is possibly because Aβ antibodies released Zn , which inhibits the ETC and reduces the
2+
do not clear toxic soluble oligomers, removing amyloid too membrane potential . This recruits dynamin-related
[60]
late in the disease process when permanent tissue damage protein 1 to mitochondria, initiating apoptosis [1,60] .
has already occurred, or because of failure to target other
elements of AD pathology such as phosphorylated tau or The role of TRPM2 in AD progression was highlighted
[1]
inflammatory mediators . in a study with cultured neurons and the APP/PS1 mouse
model. Ostapchenko et al. demonstrated increased TRPM2
Mouse models have been developed to study features
of the disease. Mice do not spontaneously develop AD; current in cultured hippocampal neurons in response
to Aβ oligomers . TRPM2 APP/PS1 mice possessed
[61]
-/-
therefore, the most common models overexpress familial decreased endoplasmic reticulum (ER) stress in brain tissue
human AD genes. This leads to amyloid plaque formation, and avoided the extensive synapse loss present in APP/
cognitive deficits, and abnormal synaptic plasticity in PS1 mice. Finally, microglial activation was decreased in
the mice [5,52] . One model is the TgCRND8 mouse, which TRPM2 AD mice. These changes were not attributable to
-/-
overexpresses mutant human APP at a rate 5 times higher altered amyloid processing in response to TRPM2 absence
than murine APP, causing plaque deposits and neuritic because the percent of amyloid plaque per tissue area
pathology by 3 and 5 months, respectively . Transgenic did not differ between TRPM2 APP/PS1 and APP/PS1
[53]

-/-
APP mice, however, do not often develop other important mice. This finding in animals is paralleled in microglial
features of the pathology, such as neurofibrillary tangles cell cultures, where TRPM2 microglial cells, or those in
-/-
and extensive neuronal and synaptic loss . For example, which the TRPM2 channel is inhibited, are not activated
[5]
by 8 months, the APP/presenilin 1 (PS1) mouse does not and do not generate tumor necrosis factor alpha (TNF-α, a
display cortical neuron loss outside the dentate gyrus . [62]
[54]
Although neuritic processes in APP/PS1 mice contain pro-inflammatory cytokine) in response to Aβ .
hyperphosphorylated tau, these do not present as tangles Although not directly related to AD, TRPM2 aged
-/-
equivalent to those in human pathology . mice (20 – 24 months old) did not demonstrate the working
[54]
Volume 1 Issue 1 (2022) 5 https://doi.org/10.36922/an.v1i1.3