Astrocytes are star-shaped cells that make up the majority of cells in the human central nervous system (CNS). They have long been known to play an important role in maintaining CNS homeostasis, including regulating neurotransmitter levels at synapses and contributing to the formation of the blood-brain barrier. Recently, it has been shown that astrocytes possess robust phagocytic ability and that they participate in the elimination of synapses and neuronal debris in the brain. Previously, microglia have been regarded as dominant phagocytes in the brain, however, recent evidence shows that astrocytic phagocytosis plays an essential role as well.
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain. Astrocytes have been found to be closely associated with these Aβ plaques, and their numbers increase as the disease progresses. It has been shown that astrocytes exposed to Aβ can increase the expression of receptors known to bind Aβ and are capable of phagocytosing Aβ. Interestingly, when reactive astrocytes are ablated in a mouse model of AD, Aβ levels increase, and memory deficits worsen, suggesting that astrocytes may contribute to the clearance of Aβ via phagocytosis.
Beclin 1, which is a protein classically associated with the autophagy pathway, was previously found to be reduced in the brains of AD patients, implying a potential connection between Beclin 1 and neurodegeneration. Beyond its role in autophagy, growing evidence suggests that Beclin 1 also regulates noncanonical pathways, including phagocytosis. Interestingly, Beclin 1 has been observed to localize to phagosomes and cellular receptors independent of autophagosomes. Notably, it was shown to regulate phagocytic receptor recycling and phagocytosis in microglia. However, whether Beclin 1 plays a similar role in astrocyte phagocytosis remained unclear.
In a new study published in the journal Tissue and Cell the role of Beclin 1 in astrocyte phagocytosis was investigated. This study was led by Associate Professor Kurt Lucin from Eastern Connecticut State University together with Associate Professor Robin White from Westfield State University and two former Eastern Connecticut State University undergraduates, Evelyn Lemus Silva (now at Harvard Medical School) and Yuberki Delgadillo (now at Lawrence and Memorial Hospital). They employed lentiviral transduction to reduce Beclin 1 levels, resulting in an approximately 80% decrease in Beclin 1 protein levels in the astrocytes. Importantly, they used a lentivirus encoding GFP, allowing them to visualize the infected cells and assess transduction efficiency. The researchers found that reducing Beclin 1 levels significantly impaired the phagocytosis of latex beads as well as the uptake of fluorescent Aβ1-42 in both C6 cells and primary astrocytes.
The research team investigated the mechanisms underlying Beclin 1-mediated astrocyte phagocytosis by studying interactions of Beclin 1 with other signaling proteins. Beclin 1 primarily partners with Vps34, a phosphatidylinositol 3-kinase (PI3K) responsible for generating phosphatidylinositol 3-phosphate (PI3P) at cellular membranes, a key event in the recruitment of proteins involved in vesicular trafficking. The authors found that reduced Beclin 1 levels resulted in decreased Vps34, impairing PI3P generation at phagosomal membranes. This, in turn, disrupted the recruitment of retromer, a protein complex involved in receptor recycling. It is important to note that retromer plays a critical role in regulating various phagocytic receptors, including Scavenger Receptor Class B type I (SR-BI). SR-BI expressed by astrocytes, was identified as a key receptor involved in the phagocytosis of Aβ when combined with amyloid-associated proteins like C1q. Intriguingly, reducing Beclin 1 levels in astrocytes led to diminished SR-BI expression. Immunocytochemistry confirmed the colocalization of SR-BI and retromer at the phagosomal membrane during latex bead phagocytosis, implying a potential role for retromer in trafficking SR-BI.
The authors’ findings shed light on a potential new mechanism by which astrocytes contribute to the clearance of Aβ in Alzheimer’s disease. Reduced Beclin 1 levels in AD patients may impair astrocyte phagocytosis, leading to the accumulation of Aβ plaques and exacerbating disease progression. The study highlights the importance of understanding the complex cellular processes involved in Aβ clearance and opens avenues for potential therapeutic strategies. While this study provides compelling evidence into the important role of Beclin 1 in astrocyte phagocytosis, several questions remain unanswered. Further research is needed to elucidate the specific mechanisms by which Beclin 1 regulates SR-BI and other phagocytic receptors in astrocytes. Additionally, understanding the factors that lead to Beclin 1 reduction in AD patients could provide valuable therapeutic targets. Indeed, strategies aimed at enhancing Beclin 1 levels in astrocytes may represent a novel therapeutic approach for AD. By promoting efficient astrocyte-mediated Aβ clearance, such interventions could potentially slow disease progression and improve cognitive outcomes. However, translating these findings from the laboratory to clinical applications will require rigorous preclinical studies in animal models and, ultimately, clinical trials.
In conclusion, the new study led by Associate Professor Kurt Lucin and his colleagues reported an important connection between Beclin 1, astrocyte phagocytosis, and Alzheimer’s disease. By demonstrating that Beclin 1 plays a crucial role in regulating astrocyte phagocytosis and identifying its impact on the phagocytic receptor SR-BI, the authors provided valuable insights into the complex cellular processes involved in Aβ clearance. Moreover, these findings may pave the way for new innovative therapeutic strategies to combat Alzheimer’s disease.
Lemus Silva EG, Delgadillo Y, White RE, Lucin KM. Beclin 1 regulates astrocyte phagocytosis and phagosomal recruitment of retromer. Tissue Cell. 2023 Jun;82:102100. doi: 10.1016/j.tice.2023.102100.