8 сентября 2026
HIF-2α Depletion and HIF-1α Overexpression in Vulnerable Brain Regions Distinguish Alzheimer’s Disease with Cerebral Amyloid Angiopathy
Vladimir S. Sukhorukov , Tatiana I. Baranich , Olga V. Velts , Kseniia M. Okulova , Dmitry N. Voronkov , Ekaterina V. Shcherbak , Anna V. Egorova , Natalia M. Mudzhiri, Dmitry S. Lazarev, Alexander P. Raksha , Alexander N. Yatskovskiy , Valeria V. Glinkina and Michail A. Piradov
Int. J. Mol. Sci. 2026, 27(17), 7784; https://doi.org/10.3390/ijms27177784
Hypoxia-inducible factors (HIF-1α, HIF-2α, HIF-3α) regulate cellular adaptation to oxygen
deprivation, but their region-specific roles in Alzheimer’s disease (AD) and AD with
cerebral amyloid angiopathy (CAA) remain unclear. Using post-mortem human brain
tissue from aging, AD, and AD + CAA groups, we measured all three HIF isoforms in
hippocampal subfields (CA1, CA2, CA4, dentate gyrus) and anterior cingulate cortex (ACC)
layers 3 and 5. In the AD hippocampus, two distinct patterns emerged: ischemia-resistant
regions (CA4, DG) maintained HIF-2α and showed relative resilience, whereas vulnerable
regions (CA1, CA2) exhibited HIF-1α upregulation, HIF-3α loss, and HIF-2α dysregulation.
The ACC contrasts sharply with the hippocampus by preserving coordinated HIF-1α/HIF3α regulation during aging and AD, with layer-specific divergence (exhaustion in layer 3
vs. resilience in layer 5) emerging only upon addition of CAA. Notably, HIF-2α in ACC
neurons remains stably elevated across all conditions. Taken together, our results highlight
HIF-2α as a potential contributor to regional vulnerability and raise the possibility that
maintaining HIF-2α levels, in addition to or instead of modulating HIF-1α, could be worthy
of further investigation in the context of AD and related vascular changes.