Mechanistic Insights into the Hypoxia-Inducible Factor-1 Paradox in Alzheimer’s Disease: A Double-Edged Sword in Neurodegeneration
Year: 2026
Type: article
Abstract: Background/Objectives: Alzheimer's disease (AD), one of the most prevalent neurodegenerative disorders in elderly, characterized by progressive cognitive loss, amyloid-β (Aβ) plaque deposition, and neurofibrillary tangle formation. Cerebral hypoxia has been reported as a complex modulator to AD pathology, with hypoxia-inducible factor-1 (HIF-1) emerging as a central molecular marker associated with neurodegeneration. This review aims to comprehensively report the roles of HIF-1 signaling in AD pathogenesis, emphasizing its neuroprotective and neurotoxic mechanisms along with demonstrating the therapeutic potential and challenges of translating this pathway for AD therapeutics. Methods: A comprehensive literature search was conducted across PubMed, Scopus, Web of Science, Embase, and Google Scholar databases for articles published between January 2000 and December 2025 on the context. Results: Under mild hypoxic conditions, HIF-1 activation enhances neuronal survival through upregulation of glucose transporters, glycolytic enzymes, angiogenic factors, erythropoietin, and antioxidant defense mechanisms. In contrast, chronic hypoxia modulates HIF-1 into a pathogenic marker through transcriptional activation of β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) and γ-secretase, facilitating amyloidogenic APP processing, along with facilitating tau hyperphosphorylation. Moreover, HIF-1 exacerbates neuroinflammation through microglial activation and pro-inflammatory cytokine release. The cell-type-specific expression patterns of HIF-1α and the temporal dynamics of its activation regulate whether the pathway exerts neuroprotective or neurodegenerative effects. Conclusions: This review discusses current understanding of HIF-1 mediated mechanistic insights in AD pathology and impacts of existing HIF-1 modulators on AD pathology along with the therapeutic implications of targeting this pathway for translational application in AD therapeutics.
Source: BioChem
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,207
OpenAlex ID: W7169782796