Decreased miR-451a in cerebrospinal fluid, a marker for both cognitive impairment and depressive symptoms in Alzheimer's disease

Abstract

Background: Alzheimer's disease (AD) patients are often accompanied by depressive symptoms, but its underlying mechanism remains unclear. The present study aimed to explore the potential role of microRNAs in the comorbidity of AD and depression. Methods: The miRNAs associated with AD and depression were screened from databases and literature and then confirmed in the cerebrospinal fluid (CSF) of AD patients and different ages of transgenic APP/PS1 mice. AAV9-miR-451a-GFP was injected into the medial prefrontal cortex (mPFC) of APP/PS1 mice at seven months, and four weeks later, a series of behavioral and pathological analyses were performed. Results: AD patients had low CSF levels of miR-451a, which was positively correlated with the cognitive assessment score, but negatively with their depression scale. In the mPFC of APP/PS1 transgenic mice, the miR-451a levels also decreased significantly in the neurons and microglia. Specific virus vector-induced overexpression of miR-451a in the mPFC of APP/PS1 mice ameliorated AD-related behavior deficits and pathologies, including long-term memory defects, depression-like phenotype, β-amyloid load, and neuroinflammation. Mechanistically, miR-451a decreased the expression of neuronal β-secretase 1 of neurons through inhibiting Toll-like receptor 4/Inhibitor of kappa B Kinase β/ Nuclear factor kappa-B signaling pathway and microglial activation by inhibiting activation of NOD-like receptor protein 3, respectively. Conclusion: This finding highlighted miR-451a as a potential target for diagnosing and treating AD, especially for those with coexisting symptoms of depression.

Altered Extracellular Vesicle miRNA Profile in Prodromal Alzheimer’s Disease

“…Other studies revealed a direct association of miR-17, miR-19b, miR-20a, and miR106a with aging and age-related conditions [47][48][49]. Furthermore, our study was also in line with recent findings that revealed the deregulation of some miRNAs in AD patients compared to healthy controls as well as using AD mouse models [3,14,[50][51][52][53][54][55][56]. It is notable that Wei and his collaborators found that the miR-233 in AD patients was correlated with cognitive decline [54].…”

“…Then, miR-195 was found to modulate the expression of BACE1 [59], whereas miR-451a decreased the expression of neuronal β-secretase 1 in neurons [50]. In addition, a downregulation of miR-451a in the CSF of AD patients, which was correlated with cognition, was also found [50]. Overall, these data suggested that some plasma EV-associated miRNAs might be useful to better characterize AD pathology.…”

“…Other studies had investigated the role of miR-16 in AD and its mechanism of action, demonstrating that genes encoding for APP and SERT (serotonin transport) were identified as two of its targets [56][57][58]. Then, miR-195 was found to modulate the expression of BACE1 [59], whereas miR-451a decreased the expression of neuronal β-secretase 1 in neurons [50]. In addition, a downregulation of miR-451a in the CSF of AD patients, which was correlated with cognition, was also found [50].…”

A cingulate-hippocampal circuit mediates early depressive-like behavior in the mouse model of Alzheimer disease

“… 37 , 38 Abnormal Aβ levels are increasingly believed to be responsible for both early mild cognitive impairment and affective symptoms. 39 , 40 At the same time, the presence of amyloid plaques in the early stages of AD directly affects functional connectivity, which impairs neuronal networks implicated in depression. 41 Consistent with the findings in AD patients, 20 , 42 we found that 5×FAD mice at early stage without cognition defects but exhibit depressive-like behaviors and display the increased Aβ accumulation in both the ACC and vCA1 compared with WT controls.…”

Potential Application of MicroRNAs and Some Other Molecular Biomarkers in Alzheimer’s Disease

“…Protective function, inhibition of BACE1, inhibition of inflammatory processes by negative regulation of NLRP3 Human cerebrospinal fluid, APP/PS1 transgenic mice, wild-type mice, mouse line Neuro-2a, human line HEK293, [98] miRNA-485-3p In summary, miRNAs exhibit the potential to modulate the onset and progression of Alzheimer's disease by regulating the molecular mechanisms involved in AD pathogenesis. Therefore, they represent promising candidates for therapeutic interventions and diagnostic applications in AD.…”