Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis

Abstract

Background One of the key pathological hallmarks of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide into amyloid plaques. The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD and has been shown to influence the accumulation of Aβ in the brain in an isoform-dependent manner. ApoE can be produced by different cell types in the brain, with astrocytes being the largest producer of apoE, although reactive microglia also express high levels of apoE. While studies have shown that altering apoE levels in the brain can influence the development of Aβ plaque pathology, it is not fully known how apoE produced by specific cell types, such as astrocytes, contributes to amyloid pathology. Methods We utilized APOE knock-in mice capable of having APOE selectively removed from astrocytes in a tamoxifen-inducible manner and crossed them with the APP/PS1-21 mouse model of amyloidosis. We analyzed the changes to Aβ plaque levels and assessed the impact on cellular responses to Aβ plaques when astrocytic APOE is removed. Results Tamoxifen administration was capable of strongly reducing apoE levels in the brain by markedly reducing astrocyte apoE, while microglial apoE expression remained. Reduction of astrocytic apoE3 and apoE4 led to a large decrease in Aβ plaque deposition and less compact plaques. While overall Iba1+ microglia were unchanged in the cortex after reducing astrocyte apoE, the expression of the disease-associated microglial markers Clec7a and apoE were lower around amyloid plaques, indicating decreased microglial activation. Additionally, astrocyte GFAP levels are unchanged around amyloid plaques, but overall GFAP levels are reduced in the cortex of female apoE4 mice after a reduction in astrocytic apoE. Finally, while the amount of neuritic dystrophy around remaining individual plaques was increased with the removal of astrocytic apoE, the overall amount of cortical amyloid-associated neuritic dystrophy was significantly decreased. Conclusion This study reveals an important role of astrocytic apoE3 and apoE4 on the deposition and accumulation of Aβ plaques as well as on certain Aβ-associated downstream effects.

A multi-pronged human microglia response to Alzheimer’s disease Aβ pathology

“…10g, h), suggesting an inability to transition from DAM towards HLA, and therefore to a full response to Ab plaques. Despite APOE4 being the major genetic risk factor for AD, our data suggest that its cell-autonomous role in microglia is rather limited, probably reflecting the fact that it operates across multiple cell types as recently shown for example for astrocytes and microglia 35,36 . As shown above, the main effect of ApoE knock out models on microglia responses seems non-cell autonomous via the decreased accumulation of amyloid-b plaques.…”

Astrocytes in Neurodegeneration: Inspiration From Genetics

“…In the AD mouse model, removing APOE ε4 reduced microglial activation and alleviated Aβ deposition in the cortex (Mahan et al, 2022). Interestingly, knocking out APOE ε4 in microglia did not affect Aβ plaque or transcriptional expression compared to controls (Henningfield et al, 2022), indicating that other glial cells, such as astrocytes, play essential roles in Aβ production and accumulation, while microglia appears to maintain Aβ homeostasis.…”

The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease

“…RNA-Sqe analysis showed that induced pluripotent stem cells carrying the APOE4 allele express lower levels of genes related to lymphatic markers, implying APOE4 might play a key role in meningeal lymphosclerosis (e.g., the premature shrinkage of mLVs) and then result in impaired meningeal lymphatic clearance [ 54 ]. The finding that selective reduction of astrocytic APOE4 strongly protected against tau-mediated and A-β-accumulated neurodegeneration also indirectly supported this evidence [ 55 , 56 ]. Taking into account these evidences, we proposed a new insight that APOE4-induced cholesterol dysregulation may herald a novel mechanism of CSVD by regulating the dysfunction of the glymphatic-mLVs system.…”