Neuroinflammation in Alzheimer’s disease: microglial signature and their relevance to disease

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, pathologically characterized by senile plaques and neurofibrillary tangles (NFTs), resulting in neurodegeneration. Neuroinflammation, defined as the activation of glial cells such as microglia and astrocytes, is observed surrounding senile plaques and affected neurons in AD. Recently conducted genome-wide association studies (GWAS) indicate that a large section of identified AD risk genes are involved in immune responses and are enriched in microglia. Microglia are innate immune cells in the central nervous system (CNS), which are involved in immune surveillance and maintenance of homeostasis in the CNS. Recently, a novel subpopulation of activated microglia named as disease-associated microglia (DAM), also known as activated response microglia (ARM) or microglial neurodegenerative phenotype (MGnD), was identified in AD model mice. These microglia closely associate with β-amyloid (Aβ) plaques and exhibit characteristic gene expression profiles accompanied with reduced expressions of homeostatic microglial genes. However, it remains unclear whether decreased homeostatic microglia functions or increased DAM/ARM/MGnD functions correlate with the degree of neuronal loss in AD. To translate the results of rodent studies to human AD, precuneus, the brain region vulnerable to β-amyloid accumulation in preclinical AD, is of high interest, as it can provide novel insights into the mechanisms of microglia response to Aβ in early AD. In this study, we performed comparative analyses of gene expression profiles of microglia among three representative neurodegenerative mouse models and the human precunei with early AD pathology. We proceeded to evaluate the identified genes as potential therapeutic targets for AD. We believe that our findings will provide important resources to better understand the role of glial dysfunction in AD.

Mesenchymal Stem Cell (MSC)-Based Drug Delivery into the Brain across the Blood–Brain Barrier

“…In AD treatment, MSCs are often used as a regenerative medicine to differentiate into neurons or Schwann cell-like cells [ 62 ]. It has been suggested that neuroinflammation triggered by activated microglial cells plays a key role in the pathogenesis of AD [ 63 ]. Moreover, it is well-known that IL-10 deficiency exacerbates inflammation-induced tau pathology [ 64 ].…”

The role of neuroinflammation in neurodegenerative diseases: current understanding and future therapeutic targets

“…Neurodegenerative diseases associated with neuroinflammation encompass a category of diseases that affect the spinal cord and the brain resulting in progressive degeneration of neural tissue and mortality (Sobue et al, 2023). In these diseases, there is a release of immune cells into the CNS causing inflammation and resulting in the degeneration of the neural tissues.…”

“…AD is marked by a continuous degenerative process, initially presenting with memory impairment, and subsequently leading to cognitive decline that can affect behavior, language, visuospatial orientation, and ultimately the motor system. As shown in Figure 2, the neuropathological characteristics of AD include extracellular Aβ(amyloid beta) plaques and intracellular hyperphosphorylated tau (p-τ) forming neurofibrillary tangles, accompanied by synaptic and neuronal loss (Sobue et al, 2023). Neuroinflammation in AD occurs when glial cells, mainly microglia and astrocytes, get activated.…”

Screening Techniques for Drug Discovery in Alzheimer’s Disease

“…Though these are the widely accepted causes of AD, there are various hypotheses in understanding AD pathology which targets several mechanisms mainly Aβ-induced neurotoxicity, tau pathogenesis, and neuroinflammatory pathways. − The heterogeneous nature of AD complicates its diagnosis, prognosis, treatment, and drug design.…”