The role of astrocytes as beta-amyloid degrading glial cells : implications for alzheimer's disease
Year: 2011
Type: dissertation
Abstract: Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder and the most common form of dementia.In AD, aggregated, cytotoxic β-amyloid (Aβ) peptides impair neuronal function and lead to a decline in memory and other cognitive functions.Other pathological hallmarks are intracellular neurofibrillary tangles, neuroinflammatory condition of Aβ-associated activated glial cells and severe neuronal and synaptic loss.Astrocytes and microglia are the most abundant glial cells in the brain being involved in homeostasis and they regulate numerous immunomodulatory and neurotrophic functions.They also share the capacity of being able to degrade Aβ. Adult astrocytes can break down Aβ spontaneously in vitro and ex vivo whereas the capacity of microglia for this effect is very limited without specific stimulation.Furthermore, the evidence for astrocyte-mediated Aβ degradation in vivo has remained inadequate.The present thesis focused on the role of astrocytes in the clearance of Aβ in experimental models of AD.Cultured adult mouse astrocytes were found to significantly reduce the Aβ burden in human AD brain sections, in contrast to the situation in neonatal astrocytes.However, after 1-7 days' follow-up time, both transplanted adult and neonatal astrocytes internalized Aβ deposits in the hippocampi of an Aβ-overproducing AD mouse model (APdE9).Mature astrocytes were also transplanted into 12 month and 23-24-month-old APdE9 mouse hippocampi.After a two months' follow-up time, the Aβ burden was significantly reduced in astrocyte-transplanted APdE9 mice compared to PBS-injected APdE9 mice.Numerous transplanted astrocytes had taken up Aβ, become apoptotic and were surrounded by phagocytic microglia.The transplanted astrocytes also expressed Aβ degrading proteases neprilysin, angiotensin-converting enzyme-1 and endothelin converting enzyme-2.These proteases were confirmed to be involved in Aβ degradation by adult astrocytes as assessed in an ex vivo assay.Surprisingly, the proteases spontaneously secreted from both neonatal and adult astrocytes efficiently degraded synthetic Aβ1-42.These proteases belonged to the serine protease family, but in neonatal astrocytes, also secreted metalloproteases and aspartyl peptidases degraded Aβ1-42 to some extent.Finally, differences in gene expression profiles between adult and neonatal astrocytes were examined after growing the cells on APdE9 or wild-type brain sections.The number of genes with altered expression was notably greater in adult astrocytes; in these cells some of the up-regulated genes related to Aβ degradation, endocytosis and anti-oxidative function in response to APdE9 section.qRT-PCR analysis confirmed the alteration in gene expression of key Aβ degrading peptidases, scavenger receptors and cholesterol synthesis.The thesis clarifies the role of astrocytes as cells contributing to Aβ catabolism in AD like conditions and reveals important factors related to maturation stages of astrocytes and their responses to different forms of human Aβ aggregates.Astrocytes are capable of substantially clearing Aβ from the brain, i.e. astrocyte-mediated Aβ clearance may represent a potential therapeutic strategy for AD.
Author: Rea Pihlaja
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3097011394