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Review
. 2021 May 31;22(11):5900.
doi: 10.3390/ijms22115900.

Elevating the Levels of Calcium Ions Exacerbate Alzheimer's Disease via Inducing the Production and Aggregation of β-Amyloid Protein and Phosphorylated Tau

Pei-Pei Guan  1 , Long-Long Cao  1 , Pu Wang  1
Affiliations
Review

Elevating the Levels of Calcium Ions Exacerbate Alzheimer's Disease via Inducing the Production and Aggregation of β-Amyloid Protein and Phosphorylated Tau

Pei-Pei Guan et al. Int J Mol Sci. .

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease with a high incidence rate. The main pathological features of AD are β-amyloid plaques (APs), which are formed by β-amyloid protein (Aβ) deposition, and neurofibrillary tangles (NFTs), which are formed by the excessive phosphorylation of the tau protein. Although a series of studies have shown that the accumulation of metal ions, including calcium ions (Ca2+), can promote the formation of APs and NFTs, there is no systematic review of the mechanisms by which Ca2+ affects the development and progression of AD. In view of this, the current review summarizes the mechanisms by which Ca2+ is transported into and out of cells and organelles, such as the cell, endoplasmic reticulum, mitochondrial and lysosomal membranes to affect the balance of intracellular Ca2+ levels. In addition, dyshomeostasis of Ca2+ plays an important role in modulating the pathogenesis of AD by influencing the production and aggregation of Aβ peptides and tau protein phosphorylation and the ways that disrupting the metabolic balance of Ca2+ can affect the learning ability and memory of people with AD. In addition, the effects of these mechanisms on the synaptic plasticity are also discussed. Finally, the molecular network through which Ca2+ regulates the pathogenesis of AD is introduced, providing a theoretical basis for improving the clinical treatment of AD.

Keywords: Alzheimer’s disease; calcium ions; mechanisms; review; transporters.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Aβ is involved in regulating Ca2+ influx via modulating Ca2+ transporters on the neuronal membranes, which result in depressing LTP and inducing cognitive decline of AD animals. Aβ can activate Ca2+ transporters, including NMDAR, AMPAR, LTCC, Na+/K+-ATPase, CALHM1, TRPV1 and Cav1.2 etc., which result in promoting Ca2+ entry into the cytoplasm, leading to elevate the concentration of Ca2+ in the neuronal cells. In addition, oligomeric Aβ can not selectively increase Ca2+ permeability of cell membrane, leading to the influx of Ca2+ from the extracellular space. More importantly, these transporters of Ca2+ have the ability to mediate the effects of Ca2+ on the synaptic plasticity via different mechanisms.
Figure 2
Figure 2
Ca2+ channels in the ER involved in regulating phosphorylation of tau, production of Aβ, which deposited in APs and NFTs, leading to impair learning ability via influencing synaptic plasticity. The accumulation of Aβ in the neuronal cells induces the Ca2+ influx from the intracellular Ca2+ store, ER. In addition, Ca2+ depletion from ER triggers a sustained extracellular Ca2+ influx to the cytosol via a SOCE pathway, including TRPC1 and Orai1 by activating the STIM. During these processes, InsP3R and RyR2 played important roles in inducing Ca2+ influx from ER to cytosol, which results in regulating synaptic plasticity, phosphorylation of tau, deposition of Aβ, leading to cognitive impairment.
Figure 3
Figure 3
The mechanisms of Ca2+ transportation between mitochondria and ER. Ca2+ is taken up to the mitochondria via MCU. Under physiological or pathological conditions, Ca2+ is continuously shuffled between ER and mitochondria via VDAC. Moreover, Ca2+ in mitochondria induces the formation of mPTP, which traversed Ca2+ and small molecules, such as ROS and cytochrome C from mitochondria to cytosol, leading to the potential apoptosis of neurons. The loss of neurons will cause the cognitive dysfunction. Deficient or mutation: Defective PS1 due to exon 9 deletion (ΔE9), as well as PS1M146V or PS1L286V mutations, lead to Ca2+ flow to mitochondria via mitochondria associated endoplasmic reticulum membrane, (MAM), which further promotes apoptosis.
Figure 4
Figure 4
Ca2+ potentially contribute to regulate the degradation of Aβ and the deposition of hyperphosphorylated tau via its transporters, including v-ATPase and TRPML1 etc., in the membrane of lysosome. TRPML1 and v-ATPase are responsible for inducing the efflux of Ca2+ from lysosome. The accumulation of Ca2+ in the cytosol can stimulate the phosphorylation of tau in the neurons, leading to the deposition of hyperphosphorylated tau in NFTs. In addition, the loss of PS1 induces the release of Ca2+ into the cytosol via TRPML1, which results in blocking the fusion between autophagosome and lysosome, leading to prevent the degradation of Aβ.
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