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 ).…”

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.…”

Human iPSC-derived astrocytes transplanted into the mouse brain undergo morphological changes in response to amyloid-β plaques

“…In AD mouse models, astrocytes show an inflammatory and neurotoxic profile together with a reduced expression of genes involved in neuronal support and communication [ 12 – 14 ], and display aberrant calcium dynamics [ 15 ]. Moreover, reactive astrocytes in AD mice increase oxidative stress and formation of reactive-oxygen species (ROS), show mitochondrial dysfunction [ 16 ] and enhance the release of neurotransmitters including glutamate, GABA and ATP [ 17 ]. These morphological, molecular and functional alterations highlight the potential importance of these cells in the pathogenesis and progression of AD.…”