Reactive astrocytes as treatment targets in Alzheimer's disease—Systematic review of studies using the APPswePS1dE9 mouse model

Abstract

Astrocytes regulate synaptic communication and are essential for proper brain functioning. In Alzheimer's disease (AD) astrocytes become reactive, which is characterized by an increased expression of intermediate filament proteins and cellular hypertrophy. Reactive astrocytes are found in close association with amyloid‐beta (Aβ) deposits. Synaptic communication and neuronal network function could be directly modulated by reactive astrocytes, potentially contributing to cognitive decline in AD. In this review, we focus on reactive astrocytes as treatment targets in AD in the APPswePS1dE9 AD mouse model, a widely used model to study amyloidosis and gliosis. We first give an overview of the model; that is, how it was generated, which cells express the transgenes, and the effect of its genetic background on Aβ pathology. Subsequently, to determine whether modifying reactive astrocytes in AD could influence pathogenesis and cognition, we review studies using this mouse model in which interventions were directly targeted at reactive astrocytes or had an indirect effect on reactive astrocytes. Overall, studies specifically targeting astrocytes to reduce astrogliosis showed beneficial effects on cognition, which indicates that targeting astrocytes should be included in developing novel therapies for AD.

The Role of Astrocytes in the Neurorepair Process

“…It is important to note that different isoforms of GFAP can be expressed in astrocytes, and the additional intermediate filament proteins Nestin and Vimentin may also contribute to the astrocytic cytoskeleton ( Wang and Bordey, 2008 ; Kamphuis et al, 2012 ). In different neuroinflammatory pathologies (e.g., infection, ischemia, neurodegenerative diseases, and brain trauma), an increase in GFAP expression can be observed ( Hol and Pekny, 2015 ; Pekny et al, 2016 ; Escartin et al, 2019 ; Smit et al, 2021 ). GFAP is commonly used as an astrocyte marker, although it is important to note that some other cell types inside (e.g., ependymal cells) and outside (e.g., hepatic stellate cells) the CNS cells can also have GFAP ( Liu et al, 2006 ; Wang and Bordey, 2008 ), and that some quiescent astrocytes do not have detectable levels of GFAP ( Kuegler et al, 2012 ).…”

Glial TDP‐43 and TDP‐43 induced glial pathology, focus on neurodegenerative proteinopathy syndromes

“…"Reactive astrocytes" is the umbrella term for a set of molecular and morphological states that astrocytes assume in response to brain injury and disease (Escartin et al, 2021). They demonstrate cellular hypertrophy, cytoskeleton changes, and elimination of processes, all of which may affect their critical role in synaptic transmission (Verkhratsky and Nedergaard, 2018;Escartin et al, 2021;Smit et al, 2021). While increased levels of GFAP have traditionally been used to assess for the presence of reactive astrocytes, recent work has demonstrated heterogeneity of astrocytes across brain regions, disease states, and in homeostasis (Escartin et al, 2019(Escartin et al, , 2021.…”

“…Astrocytes are also dynamic contributors to AD pathogenesis. In a murine model of AD, reactive astrocytes are found collocated with amyloid plaques, calcium signaling becomes uncoupled from neuronal signaling, and there is increased release of GABA, glutamate, and other gliotransmitters (Smit et al, 2021). Because of their roles in maintaining synaptic signaling and the blood brain barrier, it is hypothesized that reactive astrocytes with deleterious functions will make good therapeutic targets for neurodegenerative conditions (Escartin et al, 2019;Smit et al, 2021).…”

Role of Receptors in Relation to Plaques and Tangles in Alzheimer’s Disease Pathology

“…They are considered as a direct modulator of synaptic transmission and neuronal functioning, resulting into impaired cognition in AD. Thus, targeting reactive astrocytes for reducing reactive astrogliosis is considered as a potential therapeutic approach for ameliorating cognition in AD [ 211 ]. Similarly, the astrocytic circadian clock is considered as a regulator for inducing the inflammation of Chi3l1 protein.…”