Role of Hypoxia Inducible Factor-1α in Alzheimer’s Disease

Abstract

Amyloid-β (Aβ) peptides and hyperphosphorylated tau protein are the most important pathological markers of Alzheimer’s disease (AD). Neuroinflammation and oxidative stress are also involved in the development and pathological mechanism of AD. Hypoxia inducible factor-1α (HIF-1α) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. Emerging evidence has revealed HIF-1α as a potential medicinal target for neurodegenerative diseases. On the one hand, HIF-1α increases AβPP processing and Aβ generation by promoting β/γ-secretases and suppressing α-secretases, inactivates microglia and reduces their activity, contributes to microglia death and neuroinflammation, which promotes AD pathogenesis. On the other hand, HIF-1α could resist the toxic effect of Aβ, inhibits tau hyperphosphorylation and promotes microglial activation. In summary, this review focuses on the potential complex roles and the future perspectives of HIF-1α in AD, in order to provide references for seeking new drug targets and treatment methods for AD.

Evaluation of Class IIa Histone Deacetylases Expression and In Vivo Epigenetic Imaging in a Transgenic Mouse Model of Alzheimer’s Disease

“…HIF-1α can enhance Aβ generation via promoting β/γ-secretases and inhibiting α secretase. Emerging evidence has also shown that HIF-1α could be a potential therapeutic target for neurodegenerative diseases [46]. Furthermore, HIF-1α has been reported to resist Aβ-derived neurotoxicity, inhibit tau hyperphosphorylation, and cause microglial activation.…”

Circulating extracellular vesicle-containing microRNAs reveal potential pathogenesis of Alzheimer’s disease

“…HIF-1 and SHH signaling pathways also show hyperactivities in the early stage of AD. Both pathways participate in Aβ accumulation and hyperphosphorylation of tau, thus contributing to AD pathogenesis ( Li et al, 2021 ; Wang Y. Y. et al, 2021 ). Interestingly, HIF-1 and SHH signaling pathways can both be activated by inflammatory signals ( Arumugam et al, 2011 ; McGettrick and O’Neill, 2020 ), and further promote pro-inflammatory phenotype transition of macrophages/microglia, forming a positive feedback loop to aggravate neuroinflammation ( Song et al, 2018 ; McGettrick and O’Neill, 2020 ).…”

HIF-1 signalling pathway was identified as a potential new pathway for Icariin’s treatment against Alzheimer’s disease based on preclinical evidence and bioinformatics

“…Therefore, HIF-1α is the core target in the initiation of the HIF-1 pathway. Wang YY et al ( Wang et al, 2021b ) revealed an intriguing finding that HIF-1 exerted both neuroprotective and negative effects. HIF-1α could enhance Aβ generation by promoting β/γ-secretases and inhibiting α-secretases, as well as inactivating microglia, to promote AD pathogenesis.…”

“…HIF-1α could enhance Aβ generation by promoting β/γ-secretases and inhibiting α-secretases, as well as inactivating microglia, to promote AD pathogenesis. Although the role of HIF-1 signalling in the development of AD-related neurodegeneration is rather controversial ( Chai et al, 2014 ; Guo et al, 2017 ; Kim et al, 2017 ; Lu et al, 2018 ), increasing evidence has identified HIF-1α as a potential therapeutic target for AD ( Wang et al, 2021b ). Increased HIF-1 activity and/or increased expression of HIF-1 target proteins could alleviate cognitive impairment and AD progression by regulating glycolysis and capillary blood supply ( Iyalomhe et al, 2017 ).…”