The Role of Glial Cells in Synaptic Dysfunction: Insights into Alzheimer's Disease Mechanisms

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that impacts a substantial number of individuals globally. Despite its widespread prevalence, there is currently no cure for AD. It is widely acknowledged that normal synaptic function holds a key role in memory, cognitive abilities, and the interneuronal transfer of information. As AD advances, symptoms including synaptic impairment, decreased synaptic density, and cognitive decline become increasingly noticeable. The importance of glial cells in the formation of synapses, the growth of neurons, brain maturation, and safeguarding the microenvironment of the central nervous system is well recognized. However, during AD progression, overactive glial cells can cause synaptic dysfunction, neuronal death, and abnormal neuroinflammation. Both neuroinflammation and synaptic dysfunction are present in the early stages of AD. Therefore, focusing on the changes in glia-synapse communication could provide insights into the mechanisms behind AD. In this review, we aim to provide a summary of the role of various glial cells, including microglia, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells, in regulating synaptic dysfunction. This may offer a new perspective on investigating the underlying mechanisms of AD.

Systematic Analysis of Biological Processes Reveals Gene Co-expression Modules Driving Pathway Dysregulation in Alzheimer’s Disease

“…In the MTG, for instance, AD-induced dysregulations in synaptic functions were significantly more prevalent in neurons compared to glial cells, corroborating previous findings that implicate synaptic dysfunction as a key pathological feature of AD (10). Additionally, our observations of unique pathway dysregulations in glial cells in the MTG contribute to the emerging discourse on the role of glial cells in mediating synaptic impairment in AD etiology (144)(145)(146). In the SFG and ETC, we detect a broad downregulation of molecular pathways across multiple cell types, suggesting a more advanced and pervasive pathological state.…”

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

“…In contrast to rTg4510 and other transgenic mouse models, aging wildtype mice do not develop tau or Aβ pathology. They do, however, develop glial cell-associated neuroinflammation, which has been linked with both age-related cognitive dysfunction and tau propagation [2, 5, 43, 69, 85]. Thus, our findings could suggest that NF-κB and NLRP3 also contribute to neuroinflammation regardless of pathology.…”

“…Although aged wildtype mice do not develop tau pathology, they do develop gliosis like humans. Indeed, in human aging/AD, glial cells (astrocytes and microglia) become immune-activated, secreting cytokines that impair neuronal and cognitive function [43]. This neuroinflammation is also associated with morphological changes [44, 45], including alterations in process length [46] and branching [47, 48], which have detrimental effects on neurons (e.g., synaptic dysfunction).…”

Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice

“…Resulting neuroinflammation may likely explain synapse loss and cognitive deficits. 48 Interestingly, in a previous study evaluating the consequences of neuronal overexpression of A 2A R in a tauopathy model, the transcriptomic analysis also uncovered a microglial-related response. 27 However, despite the upregulation of microglial-selective genes in both APP/PS1 and tau transgenic mice overexpressing A 2A R, no overlap could be observed.…”