Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer’s disease patients

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of misfolded proteins, amyloid-β (Aβ) aggregates, and neuroinflammation in the brain. Microglial cells are key players in the context of AD, being capable of releasing cytokines in response to Aβ and degrading aggregated proteins by mechanisms involving the ubiquitin-proteasome system and autophagy. Here, we present in vivo and in vitro evidence showing that microglial autophagy is affected during AD progression. PDAPPJ20 mice-murine model of AD-exhibited an accumulation of the autophagy receptor p62 and ubiq-uitin+ aggregates in Iba1+ microglial cells close to amyloid deposits in the hippocampus. Moreover, cultured microglial BV-2 cells showed an enhanced autophagic flux during a 2-h exposure to fibrillar Aβ, which was decreased if the exposure was prolonged to 24 h, a condition analogous to the chronic exposure to Aβ in the human pathology. The autophagic impairment was also associated with lysosomal damage, depicted by membrane permeabilization as shown by the presence of the acid hydrolase cathepsin-D in cytoplasm and altered LysoTracker staining. These results are compatible with microglial exhaustion caused by proinflammatory conditions and persistent exposure to aggregated Aβ peptides. In addition, we found LC3positive autophagic vesicles accumulated in phagocytic CD68+ microglia in human AD brain samples, suggesting defective autophagy in microglia of AD brain. Our results indicate that the capacity of microglia to degrade Aβ and potentially other proteins through autophagy may be negatively affected as the disease progresses. Preserving autophagy in microglia thus emerges as a promising approach for treating AD.

Vasculo-Neuronal Coupling and Neurovascular Coupling at the Neurovascular Unit: Impact of Hypertension

“…The most common form of dementia is AD, a multifactorial neurodegenerative disease (Pomilio et al, 2020). Early presentations of AD include neurovascular dysfunction and microvasculature alterations (Sagare et al, 2013).…”

Physical Activity Protects the Pathological Alterations of Alzheimer’s Disease Kidneys via the Activation of PACAP and BMP Signaling Pathways

“…Amyloidogenesis is a well-controlled process in healthy tissues, but pathologic amyloid plaques can accumulate in various tissues in Alzheimer's disease (Whelly et al, 2012;Reglodi et al, 2018c). Accumulation of amyloid plaques has also been identified in peripheral organs, resulting in a systemic disorder (Morris et al, 2014;Reglodi et al, 2018c;Pomilio et al, 2020). Among others, Aβ aggregation pathologically alters pancreatic function (Kawarabayashi et al, 1996;Arbor et al, 2016;Tavares et al, 2017) and can negatively affect renal function (Kheirbakhsh et al, 2018).…”

“…Alzheimer’s disease (AD), a degenerative process in the central nervous system (CNS), is the most frequent cause of dementia in elderly patients, resulting in neuronal loss and leading to progressive cognitive deficit ( Burns and Iliffe, 2009 ; Dong Y. et al, 2019 ; Nazarian et al, 2019 ; Cervellati et al, 2020 ; Pomilio et al, 2020 ). Because of its increased prevalence, AD is one of the major priorities of healthcare systems, and various attempts have been made in the last decades to find reliable prevention methods or novel therapeutic approaches ( Belghali et al, 2017 ; Panda and Jhanji, 2019 ; Whitehouse, 2019 ).…”

Secretory Autophagy and Its Relevance in Metabolic and Degenerative Disease

“…The complete process reflects a severe imbalance between production, secretion, aggregation, and clearance of Aβ which progresses until the most advanced stages of the disease. Some studies have shown that autophagy plays a critical role in Aβ secretion (57,69). Degradative autophagy blockade is followed by Aβ intracellular accumulation which has been demonstrated to be toxic to neurons as well as degradative autophagy in microglia is deteriorated by long exposure to Aβ (69).…”

“…Some studies have shown that autophagy plays a critical role in Aβ secretion (57,69). Degradative autophagy blockade is followed by Aβ intracellular accumulation which has been demonstrated to be toxic to neurons as well as degradative autophagy in microglia is deteriorated by long exposure to Aβ (69). Moreover, the secretion of Aβ depends on autophagy, since Aβ secretion and plaque formation are reduced in mice lacking ATG7 in the excitatory forebrain neurons (57).…”