Potential Roles of Hypoxia-Inducible Factor-1 in Alzheimer's Disease: Beneficial or Detrimental?

Abstract

The major pathological characteristics of Alzheimer's disease (AD) include senile plaques and neurofibrillary tangles (NFTs), which are mainly composed of aggregated amyloid-beta (Aβ) peptide and hyperphosphorylated tau protein, respectively. The excessive production of reactive oxygen species (ROS) and neuroinflammation are crucial contributing factors to the pathological mechanisms of AD. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor critical for tissue adaption to low-oxygen tension. Growing evidence has suggested HIF-1 as a potential therapeutic target for AD; conversely, other experimental findings indicate that HIF-1 induction contributes to AD pathogenesis. These previous findings thus point to the complex, even contradictory, roles of HIF-1 in AD. In this review, we first introduce the general pathogenic mechanisms of AD as well as the potential pathophysiological roles of HIF-1 in cancer, immunity, and oxidative stress. Based on current experimental evidence in the literature, we then discuss the possible beneficial as well as detrimental mechanisms of HIF-1 in AD; these sections also include the summaries of multiple chemical reagents and proteins that have been shown to exert beneficial effects in AD via either the induction or inhibition of HIF-1.

Keywords: amyloid precursor protein (APP); amyloid-beta peptide (Aβ); microglia; neurofibrillary tangle (NFT); neuroinflammation; oxidative stress; reactive oxygen species (ROS); secretase; tau hyperphosphorylation.

Figure 1

The major pathologies in AD brains include deposition of extracellular Aβ plaques and intraneuronal neurofibrillary tangles (NFTs) mainly composed of hyperphosphorylated tau proteins. Excessive Aβ aggregation can trigger diverse mechanisms including excitotoxicity, oxidative stress with heightened ROS levels, mitochondrial dysfunction with compromised ATP production, aberrant cell cycle reentry with subsequent apoptosis, and activation of neurotoxic glial cells like microglia to trigger neuroinflammation; these effects together lead to the damage or even demise of the neurons. Tau belongs to the microtubule-associated protein (MAP) family that is vital for microtubule assembly and stabilization in neuronal axons. Hyperphosphorylated tau proteins not only compromise microtubule structures to disturb axonal transport but also aberrantly aggregate into NFTs, which also contribute to neuroinflammation and neuronal apoptosis. Excessive neuronal death ultimately results in brain atrophy in AD patients.

Figure 2

Activation of HIF-1 and its biological functions. HIF-1 is a heterodimeric transcription factor consisting of an oxygen-sensitive alpha subunit (HIF-1α) and a constitutively expressed beta subunit (HIF-1β). Under normoxia, HIF-1α undergoes hydroxylation of the proline residues catalyzed by the prolyl hydroxylase (PHD), which requires molecular oxygen (O₂). The hydroxylated HIF-1α is then recognized by the von Hippel–Lindau (VHL) protein and E3 ubiquitin ligase for ubiquitination and subsequent proteasomal degradation. Under hypoxia, low-oxygen tension interferes with PHD hydroxylation and disrupts the interaction between HIF-1α and VHL, thereby stabilizing HIF-1α for its accumulation to form the heterodimeric HIF-1α/β. Translocation of the HIF-1α/β complex into the nucleus, along with coactivators p300/CBP, then drive the expression of target genes containing the hypoxia-response element (HRE) sequences in their promoters. HIF-1-dependent gene expression is crucial for numerous cellular responses to adapt the tissues to hypoxic environments, such as promoting angiogenesis and regulating vascular tone, enhancing antioxidation, regulating glucose transport and reprogramming energy metabolisms, affecting apoptosis, and regulating immune responses.

Figure 3

Multiple AD-related mechanisms, including cerebral hypoperfusion, oxidative stress, and neuroinflammation, may trigger activation of HIF-1 to exert either positive or negative impacts on AD progression. The beneficial effects triggered by HIF-1 include affecting energy metabolisms, promoting neuroprotection/neurorestoration, enhancing neurogenesis, and counteracting oxidative stress, together allowing the tissues to adapt to the hypoxic environment. The detrimental effects include enhancing BACE1 expression with heightened β-secretase activity to promote Aβ production, impairing brain microvascular functions, and triggering neuronal cell cycle reentry followed by apoptosis. Notably, several unclear effects of HIF-1 in AD deserve detailed investigation. These include modulating brain circulation/angiogenesis, regulating tau hyperphosphorylation, affecting microglial functions and neuroinflammation, controlling the activities of α-secretase, γ-secretase, PS1/2 functions, and even Aβ degradation.