Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease

Abstract

In Alzheimer disease (AD), astrocytes undergo complex changes and become reactive. The consequences of this reaction are still unclear. To evaluate the net impact of reactive astrocytes in AD, we recently developed viral vectors targeting astrocytes that either activate or inhibit the JAK2-STAT3 pathway, a central cascade controlling astrocyte reaction. We aimed to evaluate whether reactive astrocytes contribute to Tau as well as amyloid pathologies in the hippocampus of 3xTg-AD mice, an AD model that develops Tau hyperphosphorylation and aggregation in addition to amyloid deposition. JAK2-STAT3 pathway-mediated modulation of reactive astrocytes in the hippocampus of 3xTg-AD mice, did not significantly influence Tau phosphorylation or amyloid processing and deposition, at early, advanced and terminal stage of the disease. Interestingly, inhibition of the JAK2-STAT3 pathway in hippocampal astrocytes did not improve short-term spatial memory in the Y maze but it reduced anxiety in the elevated plus maze. Our unique approach to specifically manipulate reactive astrocytes in situ show these cells may impact behavioral outcomes without influencing Tau or amyloid pathology.

Reactive astrocytes: The nexus of pathological and clinical hallmarks of Alzheimer’s disease

“…Astrocytic STAT3 knockout also corresponded to the reduced frequency of neuronal and astrocytic Ca 2+ transients as well as improved cognition in APP/PS1 mice. In contrast to these observations, inhibition of astrocytic JAK/STAT did not reduce amyloid pathology in 3xTg mice ( Guillemaud et al, 2020 ), even though effects on glial reactivity were similar to those reported in APP/PS1 mice.…”

Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway

“…To determine the molecular and functional regulation operated by STAT3 in HD reactive astrocytes, we took advantage of our viral vectors that transduce striatal astrocytes with high efficiency and selectivity ( Supplemental Fig. 1a ), to either activate or inhibit the JAK2-STAT3 pathway 39, 40 .…”

“…Viral vectors encoding murine SOCS3 or JAK2 T875N , a constitutively active form of JAK2 (JAK2ca), were used to respectively, inhibit or activate the JAK2-STAT3 pathway in mouse astrocytes 22, 39, 40 . They were co-injected with a viral vector encoding GFP or Td-Tomato to visualize transduced cells (same total viral load).…”

Astrocytes: News about Brain Health and Diseases

“…In many cases, astrocytes acquire aggressive properties, with a gain of toxic functions and loss of neurotrophic effects [ 83 , 84 ]. In other cases, however, astrocyte reactivity induces metabolic changes, including the JAK2-Stat3 cascade, contributing to reductions of amyloid deposition and restorations of defective synapses [ 85 , 86 , 87 ]. Thus, the final effects largely depend on the general state of participating astrocytes.…”

“…The majority of the recent astrocyte data regarding AD were obtained by studies of mouse brain models [ 84 , 85 , 87 , 89 , 94 ]. Additional data were obtained from mouse astrocyte lines, in some cases, duplicated with human lines or cultures [ 78 , 88 , 92 ].…”