Abstracts

Rationale: Epileptiform activity may occurrence since prodromal stage of Alzheimer's disease (AD) and exacerbate progression[1]. Calponin-3 encoded by CNN3 gene is a regulator of excitatory synaptic [2]. Previous studies indicate that calponin-3 abnormally increased in epileptic patients and animals[3]. This study aimed to explore the effect of calponin-3 on cognitive function and brain pathology in an APP/PS1 mouse model of AD.

Methods: We firstly observed the expression of calponin-3 in the hippocampi from male APP/PS1 mice. Prodromal APP/PS1 mice were injected adeno-associated virus (AAV) to interfere with hippocampal calponin-3. Four-hour electroencephalogram (EEG) were used to detect subclinical epileptiform activity. Cognition and behavior were assessed by the open field test, elevated plus-maze, new object recognition test, Morris water maze and fear condition memory test. Western Blot (WB) and immunofluorescence (IF) were conducted to investigate the AD-related molecular alterations. All procedures were approved by Animal Ethical Committee of Kunming Medical University (kmmu2021167).


Results: Hippocampal calponin-3 was significantly over-expressed and distributed in clusters and colocalized with β-amyloid (Aβ) in the APP/PS1 mice at 4,6 and 9 months of age, while that of wild type (WT) mice remained constant. Up-regulation of hippocampal calponin-3 resulted in heightened epileptiform activity and earlierly indistiguishable of the old and new locations or objects in the 4-month old APP/PS1-CNN3-OE mice. Conversely, APP/PS1-CNN3-KD mice showed significantly fewer epileptiform activity and ameliorated short-term and spatial memory at 8 months of age. Additionally, knockdown of hippocampal calponin-3 led to therapeutic benefits for Aβ metabolism, astrocyte proliferation and activation, and synaptic plasticity.


Conclusions: Hippocampal calponin-3 plays a role in regulating epilepsy and cognitive function in APP/PS1 mice, potentially representing a novel therapeutic target for AD and epilepsy comorbidity.


Funding: This work was supported by Yunnan Clinical Medical Center for Neurological and Cardiovascular Diseases(ZX2019-03-05) and Kunming Medical University joint special project(202401AY070001-008).