mGluR5 Contributionto Neuropathology in AlzheimerMice Is Disease Stage-Dependent
Figshare documentation (Figshare (United Kingdom))(2020)
摘要
Alzheimer’s
disease (AD) is the most prevalent neurodegenerative
disease and is characterized by a progressive cognitive decline in
affected individuals. Current therapeutic strategies are limited in
their efficacy and some have proven to be even less effective at later
disease stages or after extended use. We previously demonstrated that
chronic inhibition of mGluR5 signaling using the selective negative
allosteric modulator (NAM) CTEP in APPswe/PS1ΔE9 mice can rescue
cognitive function, activating the ZBTB16-mediated autophagy pathway
to reduce Aβ, the principal neurotoxic species in AD brains.
Here, we evaluated the efficacy of long-term treatment with CTEP in
6 month old APPswe/PS1ΔE9 mice for either 24 or 36 weeks. CTEP
maintained its efficacy in reversing working and spatial memory deficits
and mitigating neurogliosis in APPswe/PS1ΔE9 mice when administered
for 24 weeks. This was paralleled by a significant reduction in Aβ
oligomer and plaque load as a result of autophagy activation via ZBTB16
and mTOR-dependent pathways. However, further extension of CTEP treatment
for 36 weeks was found ineffective in reversing memory deficit, neurogliosis,
or Aβ-related pathology. We found that this loss in CTEP efficacy
in 15 month old APPswe/PS1ΔE9 mice was due to the abolished
contribution of ZBTB16 and mTOR-mediated signaling to AD neuropathology
at this advanced disease stage. Our findings indicate that the contribution
of pathological mGluR5-signaling to AD may shift as the disease progresses.
Thus, we provide the first evidence that the underlying pathophysiological
mechanism(s) of AD may unfold along the course of the disease and
treatment strategies should be modified accordingly to ensure maximal
therapeutic outcomes.
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关键词
mglur5 contributionto neuropathology,alzheimermice,stage-dependent
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