Maha Kirmani

Background: Alzheimer’s disease, primarily affecting the elderly, is characterized by Aβ plaques, Tau neurofibrillary tangles, and synaptic loss starting in the entorhinal cortex and spreading across the cortex.¹ Risk factors include age, education level, chronic stress, and elevated glucocorticoids. It has two subtypes: Sporadic/late-onset (SAD), associated with lifestyle and genetic factors like APOE4 mutations, and Familial AD (FAD), an autosomal dominant form linked to mutations in APP and presenilin. ^2,3  Recent therapeutics have focused on AB plaque clearance and symptomatic treatment, but none halt AD progression. Additionally, there is an absence of correlation between PET amyloid level and cognition function, suggesting AB may be a pathological sign of AD, rather than a cause of cognitive decline.⁴ There is increasing evidence that conjecture neuroinflammation precedes the formation of both amyloid plaques and tau protein hyperphosphorylation, activating glial cells and worsening AD progression⁵.

Objective: In this narrative review, we explored the mechanisms by which Microglia-derived EVs spread Alzheimer’s disease pathophysiology.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2024 using the following keywords: “Alzheimer’s disease”, ” extracellular-vesicles”, ” amyloid-beta”, and “microglia”.

Results: Murine microglia exposed to Aβ42 for 20 hrs and activated with 1 mM ATP released Aβ-EVs. The effects of AB-EVs derived from microglia on dendritic spines were investigated, after placing EVs on hippocampal neurons via optical tweezers. The attachment of Aβ-EVs externally induced dendritic spine thinning, favoring immature structures. Treated neurons showed impaired synaptic plasticity, lacking sustained mEPSC frequency increase compared to controls. Annexin-V coating inhibited EV extracellular movement and signaling, reducing motion by 41% and preventing LTP blockage propagation. Aβ-EVs moved extracellularly anterogradely along axonal surfaces, contrary to the retrograde motion of the control-EVs, and Annexin-V blocked this motion. To investigate Aβ-EVs’ role in spreading synaptic dysfunction, Long-term Potentiation (LTP) was measured in the entorhinal cortex (EC) and the ipsilateral Dentate Gyrus. LTP was blocked in the entorhinal cortex (EC) at both 1 hr and 24 hr intervals, spreading to the PP-DG synapse at 24 hr, suggesting that LTP impairment spread between the two interconnected regions. Unilateral injection of oligomeric Aβ42 did not propagate LTP blockage or induce lasting impairment across brain regions.⁶

Conclusions: Aβ42-enriched large extracellular vesicles (EVs) released by microglia affect dendritic spine size in cultured neurons, cause impaired synaptic plasticity within both cultured cells and brain slices, and propagate impairment of long-term potentiation (LTP) throughout the entorhinal–hippocampal circuitry. This study points to a significant role for large microglial EVs, carrying surface Aβ in the propagation of synaptic dysfunction, and can be the target for future therapeutic applications.

Works Cited:

1. Ruan Z. Extracellular vesicles drive tau spreading in Alzheimer’s disease. Neural Regen Res. 2022;17(2):328-329. doi:10.4103/1673-5374.317975
2. Gomes P, Tzouanou F, Skolariki K, et al. Extracellular vesicles and Alzheimer’s disease in the novel era of Precision Medicine: implications for disease progression, diagnosis and treatment. Exp Neurol. 2022;358:114183. doi:10.1016/j.expneurol.2022.114183
3. Zhang T, Ma S, Lv J, et al. The emerging role of exosomes in Alzheimer’s disease. Ageing Res Rev. 2021;68:101321. doi:10.1016/j.arr.2021.101321
4. Qiao Y, Chi Y, Zhang Q, Ma Y. Safety and efficacy of lecanemab for Alzheimer’s disease: a systematic review and meta-analysis of randomized clinical trials. Front Aging Neurosci. 2023;15:1169499. Published 2023 May 5. doi:10.3389/fnagi.2023.1169499
5. Gao C, Jiang J, Tan Y, Chen S. Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets. Signal Transduct Target Ther. 2023;8(1):359. Published 2023 Sep 22. doi:10.1038/s41392-023-01588-0
6. Gabrielli M, Prada I, Joshi P, et al. Microglial large extracellular vesicles propagate early synaptic dysfunction in Alzheimer’s disease. Brain. 2022;145(8):2849-2868. doi:10.1093/brain/awac083