Alzheimers Dement︱Jinjing Yao et al found a new therapeutic target for Alzheimer's disease: increased neuronal excitability mediated by type 2 nilanine receptor activity

Written by ︱ Yao Jinjing Editor ︱ Wang Sizhen Alzheimer's Disease (AD), commonly known as Alzheimer's disease, is a progressive neurodegenerative disease with insidious onset
.

AD can be divided into early-onset autosomal dominant familial AD (familial AD, FAD) and late-onset sporadic AD (sporadic AD, SAD) [1, 2]
.

FAD patients carry genetic mutations related to abnormal splicing of amyloid beta (Aβ) protein.
At present, most of our understanding of AD is based on the study of FAD-related animal models.
However, for all AD About 97% of the total cases of SAD, its pathogenic mechanism is not clear [3, 4]
.

 Although FAD and SAD may have different pathogenic mechanisms, they share some common pathological manifestations
.

The increased neuronal activity in the early stage of the disease is one of the common pathological manifestations [5-8]
.

Studies based on FAD-related animal models have shown that soluble Aβ can induce increased neuronal excitability [5, 9]
.

However, the mechanism leading to increased neuronal excitability in the early stages of SAD remains unclear
.

 Type 2 ryanodine receptor 2 (RyR2) is a calcium ion release channel existing in the endoplasmic reticulum, which is abundantly expressed in pyramidal neurons in the hippocampus and cerebral cortex [10, 11]
.

Previous studies have shown that up-regulation of RyR2 expression and enhanced function can be observed in FAD animal models at the early stage of AD and brain samples from SAD patients [12-14]
.

Therefore, the abnormal increase in RyR2 activity is likely to be one of the mechanisms leading to the upregulation of neuronal activity in AD pathological conditions
.

Preliminary work in the laboratory of Professor Wayne Chen, University of Calgary, Canada, showed that shortening the open time of RyR2 can prevent and treat AD-related neuronal damage and cognitive decline in AD mouse models (5xFAD+/-).
effect [15]
.

 On January 5, 2022, Professor Wayne Chen's lab published a paper entitled "Increased RyR2 open probability induces neuronal hyperactivity and memory loss with or The latest research results of "without Alzheimer's disease–causing gene mutations" show that simply increasing the open probability of RyR2 channels can induce a similar increase in neuronal activity and overall mouse activity without Aβ-related gene mutations.
AD-related pathological symptoms such as increased excitability, neuronal damage, and decreased learning and memory ability
.

At the same time, increasing the opening probability of RyR2 channels can make AD-related symptoms appear earlier in 5xFAD+/- mice
.

Studies suggest that the increase in neuronal excitability caused by increased RyR2 activity is likely to be one of the common pathogenic mechanisms of FAD and SAD, and it also provides a new, Aβ-independent target for the treatment of AD
.

Dr.
Jinjing Yao is the first author and co-corresponding author of this work
.

The authors first constructed transgenic mice with the RyR2-R4496C+/- (RC+/-) mutation, which increases the open probability of RyR2, and compared the mice with transgenic mice expressing calcium-sensing fluorescent protein (GCaMP6f).
Thy-1 GCaMP6f+/- was hybridized
.

The activity of CA1 pyramidal neurons in the dorsal hippocampus of mice was observed by in vivo calcium imaging
.

Observational recordings of anaesthetized and awake mice showed that neuronal activity was significantly upregulated in RC+/- mice compared with wild-type (WT) mice (Fig.
1)
.

Figure 1 RyR2-R4496C+/- mutation leads to increased excitability of hippocampal CA1 neurons (Source: Yao J, et al.
, Alzheimers Dement.
2022) At the same time, behaviors were performed on 9-11 month old RC+/- mice Academic testing
.

The results of Barnes maze (BM) experiment and novel object recognition (NOR) experiment showed that compared with WT mice of the same age, the learning and memory abilities of RC+/- mice were significantly decreased (Fig.
2 AC )
.

Further electrophysiological recordings of acutely isolated hippocampal brain slices from mice showed that the ability of CA3-CA1 projections to form long-term potentiation (LTP) in the hippocampus of RC+/- mice was significantly weaker than that of WT mice in the control group.
rat (Figure 2D,E)
.

These results indicate that simply increasing the open probability of RyR2 can lead to functional impairment of synaptic circuits in the hippocampus of mice, thereby affecting the learning and memory ability of mice
.

Figure 2 RyR2-R4496C+/- mutation leads to a decrease in the ability of learning and memory in mice (Source: Yao J, et al.
, Alzheimers Dement.
2022) The number and morphology of neurons in the hippocampus were detected by Golgi staining and Nissl staining.
, RC+/- mice showed a decrease in the density of dendritic spines in CA1 neurons similar to AD mice (Fig.
3A), and a decrease in the number of neurons in the subiculum region of the hippocampus (Fig.
3B, C).

.

Therefore, although RC+/- mice do not carry Aβ-related gene mutations, they can develop AD-related pathological phenomena such as increased neuronal excitability, neuronal damage, and decreased learning and memory abilities similar to AD model mice
.

Figure 3 RyR2-R4496C+/- mutation leads to neuronal damage in mice (Source: Yao J, et al.
, Alzheimers Dement.
2022) In addition to the above studies, in order to further confirm whether increasing the open probability of RyR2 also affects AD model mice For a similar effect, the researchers crossed RC+/- mice with 5xFAD+/- mice
.

Electrophysiological recordings, behavioral tests, and in vivo calcium imaging recordings show that RC+/- mutations can increase AD-related neuronal excitability in 5xFAD+/- mice and lead to early appearance of pathological phenomena such as decreased learning and memory abilities (Figure 4).

.

Figure 4 RyR2-R4496C+/- mutation leads to early learning and memory impairment in 5xFAD+/- mice (Source: Yao J, et al.
, Alzheimers Dement.
2022) Conclusions and discussions, inspiration and prospects This work combined in vivo calcium imaging, electrophysiology and genetic manipulation, and found that simply increasing RyR2 activity can induce AD-related pathological phenomena similar to AD mouse models without Aβ-related gene mutations
.

This suggests that increased neuronal excitability related to RyR2 activity may be one of the common pathogenic mechanisms of FAD and SAD
.

The previous work of the group showed that shortening the open time of RyR2 could prevent and reverse AD-related symptoms in 5xFAD+/- mice
.

Combining these two studies, the authors believe that regulation of neuronal excitability starting from RyR2 activity is a new target for the treatment of AD patients including FAD and SAD
.

At the same time, the latest study also shows that the increase in neuronal excitability caused by the increase of RyR2 activity is not dependent on the presence of Aβ-related gene mutations, and also shows that the RC+/- mice constructed by this work can simulate AD The pathological manifestations of the vast majority of patients with SAD
.

It provides a new method for us to understand the pathogenesis of AD more comprehensively and to study the increase of neuronal excitability related to AD
.

Combined with previous work [15] and this newly published study, it is shown that RyR2 in neurons acts as a regulator of neuron excitability.
Preliminary research on how RyR2 activity regulates neuron excitability The results show that the activity of RyR2 can regulate the excitability threshold of neurons by changing the density of A-type potassium currents on the neuron membrane, and the in-depth mechanism still needs to be further explored
.

In addition, the existing work mainly focuses on 5xFAD+/- an AD mouse model.
For other AD mouse models, whether there are consistent changes in RyR2 activity, and whether changing RyR2 activity can have the same effect is also worthy of further study.

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Link to the original text: https://alz-journals.
onlinelibrary.
wiley.
com/doi/pdf/10.
1002/alz.
12543 Dr.
Yao Jinjing (left), a research assistant at the University of Calgary, Canada, is the first author and co-corresponding author, Wayne Chen Professor (right) is the corresponding author
.

Professor Liu Yajing from Shenyang Pharmaceutical University, Professor Sun Bo from Kunming University of Science and Technology, Dr.
Zhan Xiaoqin from University of Calgary, research assistants John Estillore and Professor Ray Turner made important contributions to the article
.

This research was supported by grants from the Canadian Institutes of Health Research (CIHR)
.

(Photo courtesy of Wayne Chen's lab) Selected articles from previous articles【1】Neuron︱“Eros and Anger”: The neural substrate of female social behavior accompanied by changes in physiological state【2】Nat Neurosci︱Jingjing Liu et al.
reveal hypothalamic melanin aggregation hormone Regulation on the activity of the hippocampal-dorsolateral septal loop【3】J Neurosci︱Merlin’s lab reveals the necessary signaling pathways for generating sharp ripples and spatial working memory: NRG1/ErbB4【4】Autophagy︱Li Xiaojiang’s team discovered non-human spirit New progress in the clearance of TDP-43 cytoplasmic aggregates by SQSTM1 in long animal models【5】Nat Neurosci︱Cao Peng’s lab discovered an important function of pain in the struggle for survival among species【6】Neurosci Bull︱Tongli’s group reveals VTA - Dopaminergic neurons in the PrL neural pathway play a role in promoting wakefulness in rats under general anesthesia with sevoflurane [7] Nat Aging︱ Alzheimer's disease new discovery: a TREM2 pathway-independent bone marrow-derived macrophage Regulatory mechanism【8】Sci Transl Med︱New evidence of delayed onset of monoaminergic antidepressants: hippocampal cAMP modulates HCN channel function and then affects mouse behavior and memory【9】Nat Methods︱Peng Hanchuan research group developed cross-modal brain matching Quasi-technology, providing important support for brain atlas construction and single-cell precision whole-brain mapping research [10] Nat Commun︱Astrocytes inhibit the infiltration of peripheral macrophages in non-human primate brain ischemia injury High-quality scientific research training course Recommended【1】Single-cell sequencing and spatial transcriptomics data analysis seminar Lecture/Conference/Seminar【1】Neuroscience Bulletin online academic seminar to take you to analyze the neural system development book【1】Gift book︱Introduction to hard core brain : Scientific references on cognition and self-improvement (swipe up and down to view) 1.
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Edition by Wang Sizhen End of this paper