Microglial Beclin 1 Regulates Retromer Trafficking and Phagocytosis and Is Impaired in Alzheimer’s Disease

Abstract

SUMMARY Phagocytosis controls CNS homeostasis by facilitating the removal of unwanted cellular debris. Accordingly, impairments in different receptors or proteins involved in phagocytosis result in enhanced inflammation and neurodegeneration. While various studies have identified extrinsic factors that modulate phagocytosis in health and disease, key intracellular regulators are less understood. Here we show that the autophagy protein beclin 1 is required for efficient phagocytosis in vitro and in mouse brains. Furthermore, we show that beclin 1-mediated impairments in phagocytosis are associated with dysfunctional recruitment of retromer to phagosomal membranes, reduced retromer levels, and impaired recycling of phagocytic receptors CD36 and Trem2. Interestingly, microglia isolated from human Alzheimer’s disease (AD) brains show significantly reduced beclin 1 and retromer protein levels. These findings position beclin 1 as a link between autophagy, retromer trafficking, and receptor-mediated phagocytosis and provide insight into mechanisms by which phagocytosis is regulated and how it may become impaired in AD.

DAP12 Stabilizes the C-terminal Fragment of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) and Protects against LPS-induced Pro-inflammatory Response

“…1B). Given TREM2 is predominantly expressed in microglia in the brain (27), we sought to further confirm our findings in the immortalized murine microglial cell line BV2, a model frequently used for in vitro studies of microglial functions (28,29). Consistent with our findings in HEK293T cells, the level of TREM2-CTF was significantly elevated in the presence of DAP12 co-expression in BV2 cells (Fig.…”

Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey

“…In a recent study in mice, Safaiyan et al (2016) identified an age-related increase in Gal-3 microglia and an increase in microglia contacting myelin visualized by double-label IHC, suggesting that microglia not only have increased phagocytic activation but also that this increased activation may be related to myelin. Similar inefficient debris clearance has been seen in age-related neurodegenerative diseases such as Alzheimer's, where β-amyloid aggregation is also thought to be related to an impaired phagocytic capacity of microglia (Chung et al 1999;Lucin et al 2013;Hickman and El Khoury 2014). These data suggest that age-related impairment of microglial phagocytosis is not limited to myelin.…”

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

“…Somehow unexpectedly, retromer has been recently linked to another pathological feature of AD, namely microglia abnormalities [21]. Glia abnormalities were actually first described by Alois Alzheimer, and together with amyloid plaques and neurofibrillary tangles, is a third histological feature of the disease that bears his name.…”

“…Glia abnormalities were actually first described by Alois Alzheimer, and together with amyloid plaques and neurofibrillary tangles, is a third histological feature of the disease that bears his name. A recent study found that Vps35 is deficient in microglia harvested from AD brains and that retromer in microglia is required for the normal cell surface delivery of 2 microglia-enriched receptors-Trem2 and CD36 [21]. AD-linked variants have been found in the gene encoding Trem2 [22], and the normal cell surface delivery of CD36 is required for the microgliameditated Aβ-clearing effects.…”