Tiffany Gunnels

Background: Alzheimer disease (AD) is a neurodegenerative disease impacting the lives of more than 50 million people worldwide, and this number is expected to increase significantly by 2050.¹ Domains affected are typically memory, language, spatial cognition, and executive function.² The pathogenesis of AD is thought to progress due to Aβ oligomers (AβO) aggregating into plaques. After this, hyperphosphorylated tau forms neurofibrillary tangles leading to neurotoxicity.¹ The immune response is critical in the development of AD as microglial cells respond to neuroinflammation. Faulty responses in this process lead to increased severity of AD.³ There are currently no treatments able to slow the progression of the disease.² miRNA-34a is upregulated in AD, but the extent of its promotion pro-inflammatory phenotype has not been well described.

Objective: This review helps to connect the variety of ways miRNA-34a  impacts the microglial inflammatory response upstream of the AD amyloid plaque hypothesis.

Methods: The PubMed online database was used to find literature corresponding to the terms “Alzheimer disease”, “miRNA-34a OR miR-34a”, and “microglia”.

Results: Utilizing BV2 murine microglial cells and SHSY5Y human neuroblastoma cells, the presence of AβO induces decreased Sirt1 expression in BV2 cells and increased Sirt1 expression in SHSY5Y cells.⁵ Sirt1 is involved in the regulation of proliferator-activated receptor-gamma coactivator alpha, amyloid precursor protein, and Aβ levels.⁵ Sirt1 is a (NAD+)-dependent deacetylase, and it acts on NFB decreasing the inflammatory response of microglia.⁶ miRNA-34a represses Sirt1 expression by binding to the 3’UTR of the mRNA and targets it for degradation.⁵ In human AD patients, a set of NFB sensitive miRNAs, including miRNA-34a, were upregulated.⁵ In an inducible miRNA-34a overexpression mouse model, cognitive decline and decreased expression of Sirt1 and ADAM10 were observed. ADAM10 participates in the cleavage of the extracellular domain of TREM2.⁶ This extracellular domain is important for binding to Aβ and mediating phagocytosis to prevent further aggregation.⁷ Transgenic mice with a known human AD mutation, Trem2^R47H/R47H, demonstrated it is necessary for there to be contact between microglia and plaques in order for the previously documented gene alterations to occur.⁷ Of note, the levels of TREM2 for the mutant mice were only slightly decreased in comparison with WT.⁷ Functional TREM2 was necessary for decreased density of AβO plaques.⁷ A longitudinal study observed the levels of soluble TREM2 in autosomal dominant AD patients over the course of the disease. This study showed a correlation between increased levels of soluble TREM2 and better prognosis in pre-symptomatic individuals.⁸ Since increased levels of soluble TREM2 did not appear to confer a benefit to symptomatic individuals, TREM2 liking plays an early role in the microglial response of plaque formation.⁸

Conclusion: Upregulated miRNA-34a promotes the inflammatory phenotype by inhibiting the pro-phagocytic phenotype of microglia. This response can lead to further damage and spreading of AD pathology. Appropriate levels of Sirt1 and TREM2 are necessary for the microglial response, and modulating this enzyme and receptor could be a therapeutic strategy worth exploring. Additionally, it is necessary to enhance the specificity and sensitivity of miRNA biomarker research.

Works Cited.

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2. Knopman DS, Amieva H, Petersen RC, et al. Alzheimer disease. Nat Rev Dis Primers. May 13 2021;7(1):33. doi:10.1038/s41572-021-00269-y
3. Jorfi M, Maaser-Hecker A, Tanzi RE. The neuroimmune axis of Alzheimer’s disease. Genome Med. Jan 26 2023;15(1):6. doi:10.1186/s13073-023-01155-w
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7. Wood JI, Wong E, Joghee R, et al. Plaque contact and unimpaired Trem2 is required for the microglial response to amyloid pathology. Cell Rep. Nov 22 2022;41(8):111686. doi:10.1016/j.celrep.2022.111686
8. Morenas-Rodríguez E, Li Y, Nuscher B, et al. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer’s disease: a longitudinal observational study. Lancet Neurol. Apr 2022;21(4):329-341. doi:10.1016/S1474-4422(22)00027-8