Engagement of vascular early response genes typifies mild cognitive impairment
Pavel Katsel1, Peter Fam2, Weilun Tan1
1Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Introduction:
Molecular responses in the brains of persons with mild cognitive impairment (MCI), the earliest transitional state between normal aging and early Alzheimer's disease (AD), are poorly understood.
Methods:
We examined AD-related neuropathology and transcriptome changes in the neocortex of individuals with MCI relative to controls and temporal responses to the mild hypoxia in mouse brains.
Results:
Subsets of vascular early response to hypoxia genes were upregulated in MCI prior to the buildup of AD neuropathology. Early activation of pro-angiogenic hypoxia-inducible factor signaling in response to mild hypoxia was detected in mouse brains similar to those that were altered in MCI. Protracted responses to hypoxia were characterized by activation of phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt)-the mammalian target of rapamycin (mTOR) pathways in brain microvessel isolates.
Discussion:
These findings suggest that cerebrovascular remodeling is an important antecedent to the development of dementia and a component of the homeostatic response to reduced oxygen tension in aging prior to the onset of AD.
Insights
Brain changes in mild cognitive impairment (MCI) involve early vascular responses to hypoxia, preceding Alzheimer's disease (AD) neuropathology. This suggests cerebrovascular remodeling is key in aging and dementia development.
Area of Science:
- Neuroscience
- Pathology
- Molecular Biology
Background:
- Mild cognitive impairment (MCI) represents an early stage between normal aging and Alzheimer's disease (AD).
- Molecular brain changes in MCI are not well understood.
- Investigating these early changes is crucial for understanding dementia development.
Purpose of the Study:
- To investigate molecular responses in the brain during MCI.
- To examine neuropathology and transcriptome changes in MCI.
- To understand temporal responses to mild hypoxia in mouse brains.
Main Methods:
- Examined AD-related neuropathology and neocortical transcriptome changes in MCI individuals versus controls.
- Analyzed temporal responses to mild hypoxia in mouse brains.
- Investigated gene expression related to hypoxia and vascular remodeling.
Main Results:
- Vascular genes responding to hypoxia were upregulated in MCI before AD neuropathology accumulation.
- Early pro-angiogenic hypoxia-inducible factor signaling activated in mouse brains mirrored MCI alterations.
- Prolonged hypoxia responses involved PI3K-Akt-mTOR pathway activation in brain microvessels.
Conclusions:
- Cerebrovascular remodeling precedes dementia development.
- Hypoxia response in the brain is a component of aging homeostasis before AD onset.
- Understanding these early vascular changes may offer therapeutic targets for MCI and AD.
Related Concept Videos
01:26Alzheimer's Disease: Overview
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ...
01:30Dementia
The progression of dementia is generally gradual....