The Ambiguous Role of Microglia in Aβ Toxicity: Chances for Therapeutic Intervention

Abstract

Amyloid-β (Aβ) has long been shown to be critical in Alzheimer’s disease pathophysiology. Microglia contributes to the earliest responses to Aβ buildup, by direct interaction through multiple receptors. Microglial cells operate Aβ clearance and trigger inflammatory/regenerative processes that take place in the long years of silent disease progression that precede symptomatic appearance. But in time and with aging, the fine balance between pro- and anti-inflammatory activity of microglia deranges, negatively impacting its Aβ-clearing ability. Furthermore, in recent years, microglial activation has proven to be much more complex than the mere dichotomic pro/antiinflammatory polarization previously accepted. Microglia can display a wide spectrum of phenotypes, which can even be mixed. On these bases, it is evident that while pharmacological intervention aiding microglia to prolong its ability to cope with Aβ buildup could be extremely relevant, its feasibility is hampered by such high complexity, which still needs to be completely understood.

The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration

“…Histological studies of brains from AD patients and AD animal models show a strong colocalization of reactive glial cells with senile plaques and neurofibrillary tangles ( Parachikova et al, 2007 ; Hickman et al, 2008 ; Lopez-Gonzalez et al, 2015 ). The inflammatory cascade mechanism during AD associated with Aβ toxicity has been largely reviewed before ( Bruni et al, 2020 ; Kim et al, 2020 ; Merlo et al, 2020 ; Webers et al, 2020 ). In brief, microglia and astrocyte activation participates in Aβ clearance on AD progression’s earlier steps ( Ries and Sastre, 2016 ).…”

Promising molecular targets for pharmacological therapy of neurodegenerative pathologies

“…Many of these disorders are proteinopathies and are characterized by an accumulation of specific protein deposits, in particular Aβ in Alzheimer’s [ 48 ], resulting in the activation of immunocompetent brain cells and subsequent inflammatory reactions [ 49 , 50 ]. Thus, it has been shown that activated cells can both reduce the amount of Aβ and increase its toxic effect [ 48 , 51 , 52 ].…”

Microglia Contributes to BAF-312 Effects on Blood–Brain Barrier Stability

“…Pathological mediators or traumatic events may quickly activate microglia in response to CNS insult. The nature of microglial responses may vary: they can remove cellular debris in an attempt to contribute to cellular repair, or may precipitate the induction of the neuroinflammatory response [ 4 , 5 , 6 , 7 ]. As part of the NVU, microglial cells may modify BBB properties [ 8 ].…”