New Insights into Microglial Mechanisms of Memory Impairment in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common progressive and irreversible neurodegeneration characterized by the impairment of memory and cognition. Despite years of studies, no effective treatment and prevention strategies are available yet. Identifying new AD therapeutic targets is crucial for better elucidating the pathogenesis and establishing a valid treatment of AD. Growing evidence suggests that microglia play a critical role in AD. Microglia are resident macrophages in the central nervous system (CNS), and their core properties supporting main biological functions include surveillance, phagocytosis, and the release of soluble factors. Activated microglia not only directly mediate the central immune response, but also participate in the pathological changes of AD, including amyloid-beta (Aβ) aggregation, tau protein phosphorylation, synaptic dissection, neuron loss, memory function decline, etc. Based on these recent findings, we provide a new framework to summarize the role of microglia in AD memory impairment. This evidence suggests that microglia have the potential to become new targets for AD therapy.

Plasma microglial-derived extracellular vesicles are increased in frail patients with Mild Cognitive Impairment and exert a neurotoxic effect

“…With the progression of the disease, chronically activated microglia gradually lose their ability or efficiency to eliminate Aβ, whereas they continuously produce pro-inflammatory and neurotoxic factors as well as reactivate aberrant synaptic pruning. All these processes at the end turn to neurodegeneration [48]. In line with this, recent evidence showed that microglia is activated in the prodromal MCI phase [49], and elevated concentration of microglial EVs, positive for the myeloid marker IB4, was previously detected by flow cytometry in the CSF of MCI patients [26,50].…”

Photobiomodulation in Alzheimer’s Disease—A Complementary Method to State-of-the-Art Pharmaceutical Formulations and Nanomedicine?

“…Antioxidant therapy with vitamin C and E, even if it fails to provide effective neuroprotection, is still necessary in combination with other pharmacological or non-pharmacological methods. Another hypothesis in the pathogenesis of AD is neuroinflammation through the involvement of the partnership between microglia and astrocytes as a neuroprotective mechanism in the early stages of the disease through Aβ phagocytosis, then through the pro-inflammatory action of M1 phenotype microglia and A1 phenotype astrocytes, which release mediators with a cerebral neurotoxic effect [ 57 , 58 , 59 , 60 ].…”

Signaling pathways in macrophages: molecular mechanisms and therapeutic targets

“…AD is the most prevalent degenerative disease of the CNS and is characterized by progressive memory loss, behavioral change, and cognitive dysfunction. One of the most characteristic pathological features of AD is the deposition of Aβ and consequently the formation of neurotic plaques, which is considered by many scholars to be the initial factor of neuronal degeneration 217 . Other pathological features of AD are tau protein hyperphosphorylation and abnormal aggregation, leading to the formation of neurofibrillary tangle and the dysfunction of normal neurons and synapses.…”

“…One of the most characteristic pathological features of AD is the deposition of Aβ and consequently the formation of neurotic plaques, which is considered by many scholars to be the initial factor of neuronal degeneration. 217 Other pathological features of AD are tau protein hyperphosphorylation and abnormal aggregation, leading to the formation of neurofibrillary tangle and the dysfunction of normal neurons and synapses. Notably, activated microglia elevate tau hyperphosphorylation in a manner dependent on CX3CR1 and IL‐1/p38 MAPK 218 and drive tau propagation and toxicity via NF‐κB signaling.…”