Abstract

Objectives: To outline the underlying pathophysiology and biochemistry in Alzheimer’s Disease (AD) development and progression, and then focus on microglial effect on AD microenvironment with exploitation of microglia as a promising approach to the development of effective therapeutic for AD.

Design: In this review, a search of the literature up to December 2020 in Scopus, Web of Science, Medline, and PubMed were included, using search terms that include Aβ peptide deposition, Aβ42 protofibril, senile plaque, hyperphosphorylated tau, neurofibrillary tangles, degenerated neurons, neurodegeneration, Microgliaphenotype, microenvironments, physiological functions, phagocytosis, neuroinflammation, atrophy, frontal lobe, temporal lobes, proteolytic degradation, Biochemical imbalances, proinflammatory mediators, intracellular molecules, redox signaling molecules, Angiotensin 1 converting enzyme 1, single nucleotide polymorphisms, blood brain barrier, perivascular drainage, Low density lipoprotein receptor related protein, interstitial fluid, P-glycoprotein, cerebral amyloid angiopathy, Ubiquitin-proteasome system.

Result: Success in developing an effective therapeutic approach of AD is limited due to incompleteness of our knowledge on the biochemical and physiological effects of the initial insult inflicted by Aβ peptide deposition and senile plaques in the extracellular space. Moreover, the complexity of AD is increased by the secondary insult caused by the spatiotemporal progression of intraneuronal fibrillary tangles of hyperphosphorylated tau. Taken together, these insults contribute greatly to neurodegeneration and cognitive malfunction.

Conclusion: There is no effective treatment and no known stimulus for effective repair of degenerated neurons, neuroregeneration or prevention of neuronal death. Microglia is the main innate immune cells of the brain and detects changes in the local microenvironments to maintain normal physiological functions. Changes in the microenvironment (e.g., infection, ischaemic injury, Aβ species, Aβ-plaque, tau proteins, proinflammatory mediators), soluble factors released from neurons and astrocytes, intracellular molecules, redox signaling molecules, and metabolic shift-mediated proteins negatively impact microglial clearing processes, such as change in phenotype, morphology, and proliferative responses. An imbalance in microglia phenotypes occurs in AD with AD progression and these results in increased microglia-derived neuroinflammatory activities.

Keywords: Alzheimer’s disease; Protofibril, Ischaemic injury, Proteolytic degradation