Elevating the Levels of Calcium Ions Exacerbate Alzheimer’s Disease via Inducing the Production and Aggregation of β-Amyloid Protein and Phosphorylated Tau
Abstract
:1. Introduction
2. APP Metabolic Products Including Aβ Facilitated the Influx of Ca2+ into the Neurons of AD Animals and Patients
3. Ca2+ Transporters on the Surface of the Nerve Cell Membrane Are Responsible for Promoting the Influx of Ca2+ during the Course of AD Development and Progression
4. ER Is an Important Reservoir to Elevate the Levels of Ca2+ in the Neurons of AD
5. Mitochondria and Lysosomes Also Act as Important Organelles for Regulating the Dyshomeostasis of Ca2+ during the Development and Progression of AD
6. The Roles of Ca2+ in the Production and Deposition of Aβ during the Course of AD Development and Progression
7. Ca2+ Transporters on the Cell Membrane Are Potentially Contributed to the Role of Aβ in the Pathogenesis of AD
8. Ca2+ Leakage from ER Modulates the Production and Deposition of Aβ via Activating Ca2+ Transporters on ER
9. Ca2+ Transporters on the Membranes of Mitochondria Are Also Involved in Regulating the Production and Deposition of Aβ during the Course of AD Development and Progression
10. The Roles of Ca2+ in Regulating the Phosphorylation of Tau
11. Ca2+ Accelerates the Cognitive Decline Associated with AD
12. Transporters on the Cell Membrane Mediated the Effects of Ca2+ on Inducing the Cognitive Decline of AD
13. Ca2+ Transporters on ER Are also Involved in Impairing the Memory of AD
14. Ca2+ Transporters on Mitochondria and Lysosomes Potentially Contribute to the Memory Loss of AD
15. The Roles of Ca2+ in Synaptic Plasticity
16. Ca2+ Transporters on the Cell Membrane Are Involved in Regulating the Synaptic Plasticity
17. ER Transporters Are Responsible for Releasing Ca2+ from Internal Stores, Leading to Regulate the Synaptic Plasticity
18. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Cat. | Stimulator or Mediator | Mechanism | Experimental Model | Reference |
---|---|---|---|---|
Aβ | Aβ1–40 | Aβ1–40→IL-1β→Ca2+ influx | Rat cortical synaptosomes and cultured cortical neurons | [29] |
Aβ25–35 | Aβ25–35→L-/T-VGCC→Ca2+ influx | Rat CA1 pyramidal neurons | [31] | |
Aβ | Aβ→Ca2+ influx | APP/PS1 Tg mice | [30] | |
Aβ→PKA∪L-VGCC→Ca2+ influx | Neurons | [34] | ||
APs | Ca2+ in the spines and dendrites of cortical pyramidal neurons of APs → Ca2+ in the adjacent resting neurons. | The spines and dendrites of cortical pyramidal neurons in 3 × Tg AD animals | [22] | |
APs→Ca2+ influx | The astrocytes of 6-month-old APP/PS1 mice | [35] | ||
Aβ→Formation of cation channels→Ca2+ passage | Artificial lipid membranes | [39] | ||
Oligomeric Aβ→Ca2+ influx and leakage from intracellular Ca2+ stores | SH-SY5Y cells | [35] | ||
Aβ→Formation of pores in the cell membrane of post-mortem→Ca2+ influx | Post-mortem of AD brains | [36] | ||
sAPP | sAPP→cGMP→K+ channel┤Ca2+ | Hippocampal neurons | [56] | |
γ-secretase | γ-secretase→ER-Ca2+ | SH-SY5Y cells (control and PSEN2T122R-expressing) | [61] | |
CM | NMDAR | memantine nitrate-06 (MN-06)┤NMDAR→Ca2+ influx | Primary rat cerebellar granule hippocampal neurons | [64] |
Aβ∪endogenous Ca2+ channels→ NMDAR→Ca2+ influx | Mature hippocampal neurons | [63] | ||
AMPAR | LY451395, LY450108 and S18986┤AMPAR→Ca2+ influx | AD animal models | [69,70,71,72] | |
P/Q-VGCC | Aβ┤P/Q-VGCC→Ca2+ influx | Hippocampal neurons | [73] | |
N/T/L-VGCC | Aβ1–40→N/T/L-VGCC→postsynaptic Ca2+ response | Cortical neurons | [29,74,128] | |
Na+/K+-ATPase | Aβ┤ion-motive ATPases┤NMDAR and VGCCs→Ca2+ influx Aβ┤Ca2+-ATPase┤Ca2+ efflux | Primary neurons and synaptosomes of adult post-mortem hippocampus | [76] | |
CALHM1 | Voltage∪extracellular Ca2+→CALHM1 | hippocampal slices from wild-type Calhm1+/+, Calhm1+/−, and Calhm1−/− mice | [78] | |
APOE | APOE→G-protein-linked PLC→Ca2+ influx and mobilization | Neurons | [79] | |
APOE4>E3>E2→P/Q type Ca2+-channels→ intracellular free Ca2+ | Rat hippocampal astrocytes and neurons | [80] | ||
APOEε4→ intracellular Ca2+ | Primary cultured astrocytes of APOE−/− mice | [81] | ||
ER | Aβ/InsP3R | Aβ→InsP3R→Ca2+ response | Cultured neurons | [87] |
Aβ1–42/RyR | Aβ1–42→RyRs→Ca2+ flux | primary cultured hippocampal neurons | [88] | |
Aβ aggregates/InsP3R/RyR | Aβ aggregates→InsP3R and RyR→Ca2+ flux from ER | Human brain tissues and cells, hippocampal CA1 pyramidal neurons | [82,129] | |
PS1/InsP3R/RyR/SERCA | PS1∪InsP3R, RyR and SERCA→Ca2+ signaling cascade | Primary rat cortical neurons | [89,90,91,93,94] | |
PS/InsP3R | PS∪InsP3R→Ca2+ flux | Primary cortical neurons | [90] | |
PS1mut/InsP3 | PS1mut→PLC→InsP3→Ca2+ flux from ER | SH-SY5Y cell | [95] | |
PSmut/RyR | PSmut→InsP3R and RyR→Ca2+ release from ER | PC12 cells, mouse neurons and lipid bilayers | [93,96,130,131] | |
PSmut/SERCA | PSmut∪SERCA→Ca2+ influx | SH-SY5Y cells and patient-derived fibroblasts | [132] | |
APOE4/RyR | APOE4→RyR→Ca2+ release from ER→APs and NFTs | Rat primary hippocampal neurons | [98,99,100] | |
Stim1D76A | Stim1D76A mutation┤SOCE→Ca2+ influx | Primary neurons from the PS1mut mice | [104,105] | |
Stim2 | PS1M146V mutation┤STIM2→SOCE→Ca2+ influx | PS1M146V mice | [106] | |
Stim1 | PS1 ΔE9 mutation→Stim1→SOCE→Ca2+ influx | mouse hippocampal neurons | [107] | |
TRPC3 | BDNF→TRPC3→Ca2+ influx. | Pontine neurons and SH-SY5Y cells | [108,110] | |
TRPC6 | PS2→TRPC6┤Ca2+ influx | HEK293 cells | [109] | |
MT | PS1L286V and PS1M146L | PS1L286V mutation┤Mitochondria→Ca2+ flux | PS1L286V mutated PC12 cells and PS1M146L lymphoblasts | [111,112,113] |
VDAC | hAPPSwe→VDAC1→Ca2+ flux to the mitochondria | Tg2576 mice | [114] | |
MCU | MCU→Ca2+ flux to the mitochondrial matrix | COS-7 cell | [115,116] | |
Na+/Ca2+ exchanger | Na+/Ca2+ exchanger→Ca2+ across IMM | HEK293T cells | [117,118,119] | |
mPTP | mPTP→Efflux of Ca2+ from mitochondria | SH-SY5Y cells | [120] | |
LM | v-ATPase/CAX | V-ATPase and CAX→Ca2+ influx to lysosomes | Rat kidney fibroblasts | [122,123,133] |
TRPML/TPC | TRPML and TPC→Ca2+ efflux from lysosomes | HEK293 cells | [124] | |
VGCC | VGCC→Ca2+ release┤autophagic fusion and/or autophagy flux. | Cacna1a−/− and Cacna2d2−/− mice | [125] | |
PS1mut/− | Mutation or deletion of PS1┤v-ATPase →Ca2+ uptake by lysosomes | APP/PS1 mice | [126] | |
PS1/2−/− | PS1 and 2 knockout┤Ca2+ uptake by lysosomes→autophagy process | PS1/2−/− neurons | [127] |
Cat. | Stimulator or Mediator | Mechanism | Experimental Model | Reference |
---|---|---|---|---|
Ca2+ | Aβ | Ca2+ ionophore, A23187→free Ca2+→Aβ production | hAPP overexpressed HEK293 cells, Primary cultured neurons from 3 × Tg AD mice | [134,135,136] |
Ca2+→Aβ | SH-SY5Y cells | [36] | ||
Ca2+→Aβ1–40 oligomers | Neurons | [137] | ||
Ca2+→Aβ fibrils | AD mice and in vitro Aβ peptides | [138,139] | ||
CM | NMDAR | Memantine┤NMDAR→Aβ | SH-SY5Y cells | [138] |
AMPAR | AMPAR→Ca2+→tau phosphorylation | PS1mut mice | [140,141] | |
Memantine┤NMDAR→Aβ1–40 | APP23 mice | [142] | ||
NMDAR→ADAM10 | Primary mouse cortical neurons | [143] | ||
AMPAR | AMPAR→α-secretase→sAPPα┤Aβ | Cortical neurons | [144] | |
CALMH1 | CALHM1P86L→sAPPβ→Aβ | APP Tg mice | [138,145] | |
L-VGCC | L-VGCC→Ca2+→Aβ | Rat cortical neurons | [134,138] | |
Cav1.2 | Isradipine┤Cav1.2→Aβ | 3 × Tg mice | [34] | |
APOE4 | APOE4→Aβ42 in CSF | AD patients | [34] | |
APOE | APOE1-3┤Aβ | hAPOE isoforms (PDAPP/TRE) expressing Aβ-amyloidosis mice | [146] | |
ER | InsP3R | InsP3R−/− receptor┤Aβ | InsP3R−/− Sf9 and DT40 cells | [90] |
RyR | RyR→NFTs | AD patients, Primary cultured rat neurons | [101,147] | |
RyR→Ca2+→Aβ | βAPP expressed HEK293 cells | [134,135] | ||
Dantrolene→RyR→β-/γ-secretase→phosphorylation of APP and formation of APs | Dantrolene treated AD mice | [148,149] | ||
RyR2 | APP mutation→RyR2PTM→Ca2+ leaky┤Aβ | SH-SY5Y cells | [150] | |
FKBP12.6∪RyR2→Ca2+ leaky┤APs | 3 × Tg mice | [150] | ||
RyR3 | RyR3−/−┤APs | APP/PS1 mice | [151] | |
SERCA | Thapsigargin or siRNA┤SERCA→Aβ | PS1−/− and PS2−/− fibroblasts | [94] | |
Thapsigargin┤SERCA→Ca2+→Aβ | APP overexpressed HEK293 cells | [135] | ||
10 nM thapsigargin→Aβ 20 nM thapsigargin┤Aβ | APP overexpressed CHO cells | [152] | ||
Stim1/Orail | Stim1/Orai1→SOCE→Ca2+→Aβ/APs | APP expressed HEK293 cells | [105] | |
SOCE | SOCE→mushroom spines ┤Aβ┤memory functions | PS1M146V knockin hippocampal neurons | [153,154] | |
SOCE→Ca2+ influx ┤Aβ→AD | Human neuroblastoma cells, Primary cultured hippocampal neurons | [155,156] | ||
SOCE inhibition→Aβ1–42 | SH-SY5Y cells, Human neuroglioma H4 cells | [157,158] | ||
MT | VDAC1 | Reduced expression of VDAC1┤βAPP, Tau, PS1, PS2, and BACE1 | VDAC1+/− vs VDAC1+/+ mice | [159] |
mPTP | APPKM670/671NL/PS1L166P∪dutasteride┤mPTP→APs | Primary neurons and APP/PS1 Tg mice | [160] | |
Ca2+ | p-tau | Ca2+→p-tau | SH-SY5Y cells | [100] |
Ca2+→GSK3β→p-tau | SH-SY5Y cells | [161] | ||
Ca2+→p-tau | Primary hippocampal neurons and the immortalized GnRH neurons (GT1-7 cells). | [162] | ||
Ca2+→mPGES-1/PGE2/EPs/CDK5/p35/p25→p-tau | N2a and APP/PS1 Tg mice | [19] | ||
NFTs | Ca2+→Ca2+-activated kinases→p-tau→NFTs | SH-SY5Y, N2a and AD mice models | [100,163] |
Cat. | Stimulator or Mediator | Mechanism | Experimental Model | Reference |
---|---|---|---|---|
Ca2+ | Serum Ca2+→cognitive decline | Aging people | [174] | |
Ca2+→dementia | AD patients | [175] | ||
Aβ oligomes | Aβ oligomers→Ca2+ influx┤LTP→synaptic plasticity→learning and memory | AD models, Hippocampal slices and APP/PS1 Tg mice | [176,177,178] | |
Calpain | Inhibitor┤calpain→Aβ┤learning and memory | APP/PS1 mice | [179] | |
Calcineurin | Inhibitor┤calcineurin┤learning and memory | Tg2576 mice | [180] | |
CM | NMDAR | Calcineurin→removing NMDAR/AMPAR by endocytosis┤cognition of AD | APP/PS1 mice | [181] |
Antagonist┤NMDAR┤synaptic plasticity┤cognitive decline | Rats | [182,183] | ||
Blocking NMDAR┤Ca2+┤cognition | AD patients and AD mouse models | [184,185] | ||
CP-AMPAR→Ca2+ influx→neuronal network dysfunction/excitotoxicity→cognitive decline | APP/PS1 mice | [186] | ||
L-VGCC | L-VGCC→Ca2+ currents→cognitive decline | CA1 synapses of 3 × Tg AD mice | [187] | |
Nifedipine┤Ca2+ channel→cognitive impairment | KK-A(y) mice | [188] | ||
Nimodipine┤L-VGCC┤learning ability | Mild-to-moderate AD patients | [189] | ||
T-VGCC | ST101┤T-VGCC┤LTP/p-CaMKII →cognitive decline | Rat cortical slices | [190] | |
NMDAR | MK-801┤NMDAR→Ca2+→cognitive decline | Traumatic brain injury (TBI) mice | [191] | |
Cav 2.1 | Cav 2.1−/−┤Ca2+┤learninig ability | Cav 2.1 knocking out mice | [192] | |
TRPV1 | SB366791┤TRPV1┤cognitive performance | Dopamine D3 receptor (D3R)−/− mice | [193] | |
APOE4 | APOE4→serum Ca2+┤cognitive function | Aging people | [194] | |
CALHM1 | CALHM1P86L polymorphism→AD | Chinese populations | [195] | |
ER | InsP3 | PS1M146V┤InsP3→InsP3R1→Ca2+ →memory loss | PS1M146V mice | [196] |
InsP3R | SOCE∪InsP3R→Ca2+┤cognitive impairment | Sporadic or mild AD patients | [197] | |
RyR | Dantrolene┤RyR┤synaptic plasticity→cognitive ability | AD mouse model | [198] | |
RyR2/RyR3 | RyR3−/−/RyR2+/+┤social behavior and memory | RyR3−/−/RyR2+/+ mice | [199,200] | |
RyRPTM→ER→Ca2+ leaky →cognitive deficits | 3 × Tg mice | [150] | ||
Stim2/SOCE | STIM2−∪SOCE−┤mushroom spines→LTP→memory | PSmut mice | [106,201] | |
SOCE−→cognitive decline→AD | Hippocampal slice cultures | [202] | ||
MT | VDAC1 | VDAC1∪p-tau, Aβ, and γ-secretase→neurotoxicity→cell death→dementia→AD | APP, APP/PS1 and 3 × Tg mice | [203] |
mPTP | DS16570511, DS44170716┤MCU→Ca2+ influx to mitochondria→mPTP→apoptotic cell death | HEK293 cells | [204,205] | |
LM | TPC | Tetrandrine, NED-19┤TPCE2┤re-acidify lysosome→autophagy | MEFs cells | [206] |
Beclin1−/−→Aβ | hAPP mice | [207] |
Cat. | Stimulator or Mediator | Mechanism | Experimental Model | Reference |
---|---|---|---|---|
Ca2+ | Aβ→Ca2+ influx→LTD┤memory┤AD | Tg2576 mice | [28] | |
Aβ oligomers→Ca2+┤LTP | Hippocampal slices | [176] | ||
PS1−/−┤LTP | PS1−/− mice | [216] | ||
BAPTA-AM┤Ca2+┤LTP. | Aged rat hippocampal slices | [217] | ||
CM | CaN | CaN+┤LTP CaN−→synpatic strength →LTP | CaN+ mice | [218] |
Ca2+→CaN→LTD | Aged or APP mice | [180,219] | ||
Inhibitors┤CaN┤LTP | APP mice | [180] | ||
Aβ┤CaN┤synaptic plasticity | Tg2576 mice | [28] | ||
NMDAR | Aβ oligomers→NMDAR→Ca2+┤LTP | Hippocampal CA1 and DG regions | [220] | |
NMDAR→Ca2+┤LTP | Rat hippocampus | [221] | ||
AMPAR | AMPAR→Ca2+→LTP∪LTD | CA1 pyramidal cells | [242] | |
GluR2−/−→LTP | GluR2−/− mice | [223] | ||
CP-AMPAR→LTP | CA1 hippocampal neurons | [224] | ||
Glycine→CP-AMPAR→CaMKI→LTP | Mature hippocampal neurons | [225] | ||
Ca2+/Calmodulin∪PSD-95┤PSD-95∪AMPAR┤LTD | Rat hippocampal neurons | [226] | ||
VGCC | VGCC→CaMKII→LTP | Hippocampus slides | [227] | |
Cav1.2 | Cav1.2+→LTP, synaptic plasticity, and the memory | Ca(V)1.2 (cKO) mice | [228] | |
TRPV1 | Capsaicin and resiniferatoxin→TRPV1→LTP | Hippocampus slides | [229] | |
Capsaicin→TRPV1→Ca2+ influx→LTP | Hippocampus slides | [229] | ||
TRPV1/4 | Endocannabinoid anandamide (AEA) →TRPV1/4→LTP | CB1−/− mice TRPV1−/− mice | [230,231] | |
TRPM2 | Inhibitor┤TRPM2┤LTP | Traumatic injured brain of mice | [232] | |
TRPM4 | TRPM4−┤NMDAR→LTP | CA1 hippocampal neurons | [233] | |
ER | IP3 | IP3→Ca2+ efflux from ER→LTD | Myosin-Va mutation mice or rats | [234] |
Metabotropic glutamatergic receptors→InsP3→Ca2+ efflux from ER→LTD | Hippocampal slices | [235] | ||
InsP3R/RyR | InsP3R−→LTP∪┤LTD RyR−┤LTP∪LTD | Rat hippocampus slides, 3 × Tg AD mice | [196,243] | |
RyR | RyR3−/−→LTP∪┤LTD | RyR3−/− mice, 3 × Tg mice | [237,238] | |
PS−→RyR→Ca2+ release from ER ┤LTP | PS conditioned neurons from CA1 and CA3 | [239] | ||
SOCE | SOCE−┤Ca2+ influx→CaMKII→LTP→memory | FVB/NJ mice | [240] | |
STIM1+┤LTD┤contextual learning | FVB/NJ mice | [240] | ||
MT | VDAC | VDAC1−/−┤synaptic plasticity | VDAC1−/− mice | [159] |
mPTP | Cyclosporine A┤mPTP→long and short term synaptic plasticity | Porin-deficient or cyclosporin A-treated mice | [241] |
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Guan, P.-P.; Cao, L.-L.; Wang, P. Elevating the Levels of Calcium Ions Exacerbate Alzheimer’s Disease via Inducing the Production and Aggregation of β-Amyloid Protein and Phosphorylated Tau. Int. J. Mol. Sci. 2021, 22, 5900. https://doi.org/10.3390/ijms22115900
Guan P-P, Cao L-L, Wang P. Elevating the Levels of Calcium Ions Exacerbate Alzheimer’s Disease via Inducing the Production and Aggregation of β-Amyloid Protein and Phosphorylated Tau. International Journal of Molecular Sciences. 2021; 22(11):5900. https://doi.org/10.3390/ijms22115900
Chicago/Turabian StyleGuan, Pei-Pei, Long-Long Cao, and Pu Wang. 2021. "Elevating the Levels of Calcium Ions Exacerbate Alzheimer’s Disease via Inducing the Production and Aggregation of β-Amyloid Protein and Phosphorylated Tau" International Journal of Molecular Sciences 22, no. 11: 5900. https://doi.org/10.3390/ijms22115900