Synapses, Microglia, and Lipids in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is characterised by synaptic dysfunction accompanied by the microscopically visible accumulation of pathological protein deposits and cellular dystrophy involving both neurons and glia. Late-stage AD shows pronounced loss of synapses and neurons across several differentially affected brain regions. Recent studies of advanced AD using post-mortem brain samples have demonstrated the direct involvement of microglia in synaptic changes. Variants of the Apolipoprotein E and Triggering Receptors Expressed on Myeloid Cells gene represent important determinants of microglial activity but also of lipid metabolism in cells of the central nervous system. Here we review evidence that may help to explain how abnormal lipid metabolism, microglial activation, and synaptic pathophysiology are inter-related in AD.

Central role of microglia in sepsis-associated encephalopathy: From mechanism to therapy

“…E4-expressing microglia showed higher innate immune reactivity after LPS treatment, significantly reduced neuronal activity, and secreted more elevated levels of TNF when co-cultured with neurons ( 69 ). Microglia perform some critical functions in the brain ( 70 ) synaptic genesis, modification, and plasticity changes ( 71 ); (2) detection of local steady state ( 72 ); (3) immune function, including phagocytosis, antigen presentation, secretion of anti-inflammatory (such as IL-10, IL-4) and pro-inflammatory (such as IL-1β, IL-6) cytokines, and regulation of neuronal apoptosis ( 73 ); (4) regulation of myelin sheath ( 74 ); (5) neurotrophic support ( 75 ); and (6) communicate with astrocytes to regulate these functions ( 76 ). ( Figure 2 ) Furthermore, microglia are involved in synapses and neurogenesis, as well as in the removal of unwanted neuronal and other cellular waste.…”

Phosphatidylserine, inflammation, and central nervous system diseases

“…Alzheimer’s disease AD is a progressive neurodegenerative disease; the pathological features of AD are characterized by the accumulation of amyloid-β (Aβ) plaques and phosphorylated tau neurofibrillary tangles ( Paasila et al, 2021 ). There are many hypotheses about the mechanisms of AD, including synaptic dysfunctions hypothesis, cholinergic theory, amyloid cascade hypothesis, tau cascade hypothesis, neuroinflammation, and gut-brain axis hypotheses ( Craig et al, 2011 ; Calsolaro and Edison, 2016 ; Kowalski and Mulak, 2019 ; Ju and Tam, 2022 ).…”

Tissue-Engineered Constructions in Biophysics, Neurology and Other Fields and Branches of Medicine

“…In addition, it turned out that microglia are involved both in the process associated with neurogenesis and in the processes of memory degradation not associated with neurogenesis [ 85 – 89 ]. Literature data [ 85 – 89 ] suggest that there are grounds for complement-dependent elimination of synapses with the participation of microglia. It is possible that this mechanism is one of the mechanisms involved in the processes of forgetting distant memories [ 85 – 89 ].…”

“…Literature data [ 85 – 89 ] suggest that there are grounds for complement-dependent elimination of synapses with the participation of microglia. It is possible that this mechanism is one of the mechanisms involved in the processes of forgetting distant memories [ 85 – 89 ]. Microglial dysfunction can cause synaptic dysfunction and excessive synapse loss early in the disease, leading to a number of subsequent pathologies.…”