Beneficial versus Detrimental Effects of Complement-Microglial Interactions in Alzheimer’s Disease

Gunel Ayyubova; Nadeem Fazal

doi:10.20944/preprints202403.0872.v1

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preprints.org > medicine and pharmacology > neuroscience and neurology > doi: 10.20944/preprints202403.0872.v1

Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Beneficial versus Detrimental Effects of Complement-Microglial Interactions in Alzheimer’s Disease

Gunel Ayyubova

and

Nadeem Fazal

Version 1 : Received: 14 March 2024 / Approved: 14 March 2024 / Online: 15 March 2024 (11:21:41 CET)
Version 2 : Received: 1 April 2024 / Approved: 2 April 2024 / Online: 2 April 2024 (15:22:35 CEST)

A peer-reviewed article of this Preprint also exists.

Ayyubova, G.; Fazal, N. Beneficial versus Detrimental Effects of Complement–Microglial Interactions in Alzheimer’s Disease. Brain Sci. 2024, 14, 434. Ayyubova, G.; Fazal, N. Beneficial versus Detrimental Effects of Complement–Microglial Interactions in Alzheimer’s Disease. Brain Sci. 2024, 14, 434.

Abstract

Research indicates that brain region-specific synapse loss and dysfunction are early hallmarks and stronger neurobiological correlates of cognitive decline in Alzheimer’s disease (AD) than counts of amyloid plaques, neurofibrillary tangles, and neuronal loss. Even though the precise mechanisms underlying increased synaptic pruning in AD are still unknown, it has been confirmed that dysregulation of the balance between complement activation and inhibition is a crucial driver of pathology. The complement includes three distinct activation mechanisms, with activation products C3a and C5a, potent inflammatory effectors, and a membrane attack complex (MAC), leading to cell lysis. Besides pro-inflammatory cytokines, dysregulated complement proteins released by activated microglia bind to amyloid β at synaptic regions and cause microglia to engulf synapses. Additionally, research indicating that microglia-removed synapses are not always degenerating, and that suppression of synaptic engulfment can repair cognitive deficits point to an essential opportunity for intervention that can prevent the loss of intact synapses. In this study, we focus on the latest research on the role and mechanisms of complement-mediated microglial synaptic pruning at different stages of AD to find the right targets that could interfere with complement dysregulation and be relevant for therapeutic intervention at the early stages of the disease.

Keywords

complement proteins, cognitive decline, synapse loss, microglia, neurodegeneration

Subject

Medicine and Pharmacology, Neuroscience and Neurology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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