Alzheimer’s disease (AD)—the most common form of dementia—has been a point of intensive scientific studies due to its complex pathology and tremendous societal impact. Beyond the accumulation of amyloid-beta (Aβ) plaques and Tau protein tangles characteristic of the disease, synaptic dysfunction and loss emerge as crucial factors in the cognitive decline seen in AD patients. In a groundbreaking study published in the European Journal of Histochemistry, Xu Nan and colleagues shed light on a key regulatory mechanism in play during AD’s progression: the role of miR-132 in regulating the expression of synaptic proteins through C1q (DOI: 10.4081/ejh.2019.3008). This article elaborates on these findings and their significance in the AD landscape.
Abstract
Cognitive impairment in Alzheimer’s disease (AD) is often attributed to synaptic loss in regions such as the hippocampus and neocortex. miR-132, a microRNA abundant in the brain, plays a role in neuronal morphogenesis and plasticity, and is significantly reduced in Alzheimer’s patients. The transgenic APP/PS1 mouse model allows scientists to explore gene expression dysregulation associated with AD, and Xu Nan’s team has utilized this model to investigate the relation between miR-132 and C1q, a protein linked to synaptic integrity and AD pathology. Their findings suggest that restoring miR-132 levels or inhibiting C1q can ameliorate synaptic protein loss and potentially halt cognitive decline in AD.
Introduction
Alzheimer’s disease presents as a relentless challenge, with synaptic deterioration being a key contributor to cognitive deficits that plague affected individuals. Early stages of AD are marked by amyloid-beta induced synaptic changes, while later stages see the accumulation of Tau protein driving synapse degeneration. The intricate molecular mechanisms governing these processes have not been fully unraveled until recently, when researchers turned their focus on the role of microRNAs (miRNAs), particularly miR-132, in AD.
miR-132 and Synaptic Plasticity
miR-132 is well-documented for its contributions to neuron morphogenesis and plasticity. Acting as a fine-tuner of gene expression, miR-132 has shown to impact the central nervous system profoundly. Substantial reductions of miR-132 are observed in the brains of Alzheimer’s patients, aligning with the degrees of cognitive decline. These reductions correlate with increased Aβ deposition and Tau pathology, evidence that supports the importance of miR-132’s regulatory role in healthy neuronal function.
The Connection Between miR-132 and C1q
C1q, the initiating protein of the classical complement cascade, is highly expressed in synaptic regions of AD patients’ central nervous systems. This study by Xu Nan et al. proposes that miR-132 directly influences C1q expression. The APP/PS1 transgenic mouse model, which harbors mutations leading to AD-like pathology, served as the basis for this study. Through the transfection of miR-132 and administration of C1 inhibitors, the research team investigated the downstream effects on synaptic proteins and cognitive function in these mice.
Experiment and Results
Behavioral tests conducted seven days after the administration of miR-132 or C1 inhibitors showed that memory and cognitive abilities were markedly improved in treated mice compared to the AD group. An analysis of synaptic protein expression, namely PSD95 (postsynaptic density protein), Synapsin-1, and phosphorylated Synapsin, indicated a significant uptick in these proteins post-treatment, supporting the hypothesis that miR-132 is capable of modulating C1q expression and thereby influencing synaptic protein regulation.
Understanding RT-qPCR Results
RT-qPCR analysis further reinforced the notion that miR-132 can modulate C1q expression, highlighting a potential therapeutic target within the neuronal microRNA system. Given the avoidance of gene editing or introduction of foreign proteins, this method of regulation bears a lower risk of adverse immune responses, making it an attractive approach for future drug development strategies in mitigating AD pathology.
Conclusion and Implications for Alzheimer’s Treatment
The profound effects of miR-132 on C1q expression and synaptic protein levels suggest that miR-132 and the classical complement cascade are entwined in a complex regulatory network. Restoration of miR-132 levels or direct inhibition of C1q could be a viable strategy for sustaining synaptic integrity in the face of AD’s relentless progression.
References
1. Shankar GM, et al. (2008). Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med, 14, 837-42. DOI: 10.1038/nm1782.
2. Kim J, Yao F, Xiao Z, Sun Y, Ma L. (2018). MicroRNAs and metastasis: small RNAs play big roles. Cancer Metastasis Rev, 37, 5-15. DOI: 10.1007/s10555-017-9692-y.
3. Hernandez-Rapp J, et al. (2015). Memory formation and retention are affected in adult miR-132/212 knockout mice. Behav Brain Res, 287, 15-26. DOI: 10.1016/j.bbr.2015.02.037.
4. Lau P, et al. (2013). Alteration of the microRNA network during the progression of Alzheimer’s disease. EMBO Mol Med, 5, 1613-34. DOI: 10.1002/emmm.201201974.
5. Fonseca MI et al. (2004). Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer’s disease. J Neurosci, 24, 6457-65. DOI: 10.1523/JNEUROSCI.0901-04.2004.
Keywords
1. miR-132 Alzheimer’s disease
2. C1q complement cascade AD
3. Synaptic loss in Alzheimer’s
4. Alzheimer’s disease therapeutics
5. MicroRNA AD treatment