Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is associated with deficiencies in cerebrovascular functions, e.g. reduced cerebral blood flow and capillary amyloid angiopathy, both of which are evident during the early phase of AD, thus local hypoxia/ischemia could augment the pathogenesis of AD. There is abundant literature revealing that exposures to hypoxia/ischemia increase the amyloidogenic processing of amyloid-b precursor protein (APP) leading to the accumulation of amyloid-b peptides in brain. This hypoxia-induced response has been attributed to a significant increase in the activities of b-and csecretases, whereas a-secretase activity decreases in hypoxia. Recent studies have indicated that hypoxia-inducible factor-1a (HIF-1a) stimulates the transcription of the bsecretase 1 (BACE1) gene through the hypoxia-response element in the BACE1 promoter. Moreover, HIF-1a protein can directly interact with the c-secretase complex and increase its activity in a non-transcriptional manner. Hypoxia/ischemia also trigger endoplasmic reticulum stress and impair autophagy in brain, which consequently can stimulate the expression of presenilin 1 (PS1) and activate c-secretase. Subsequently, PS1 protein can stabilize HIF-1a protein and in addition, APP intracellular domain peptide is able to induce the expression of HIF-1a. The activation of b-and c-secretases is an evolutionarily conserved hypoxia response, e.g. it is also present in zebrafish. Given that b-and c-secretases have many substrates in addition to APP, one could postulate that AD pathology is a byproduct of the rescue process mediated by these two aspartyl proteinases under hypoxic/ischemic conditions. We will review the recent evidence indicating that vascular dysfunctions can provoke AD pathology by activating b-and c-secretases.

Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer’s Disease

“…This raises the question, however, of whether this treatment directly impacts AD pathophysiology or may it just treat an atherosclerotic comorbidity. There is evidence directly linking hypoxia to amyloidogenic processing of the amyloid-β protein precursor (AβPP) [52]. Hypoxia-inducible factor-1α (HIF-1α) leads to increased β-secretase 1 (BACE-1) transcription, which occurs through HIF-1α binding to the hypoxia-responsive element in the promotor region of the BACE-1 gene [53].…”

“…Hypoxia-inducible factor-1α (HIF-1α) leads to increased β-secretase 1 (BACE-1) transcription, which occurs through HIF-1α binding to the hypoxia-responsive element in the promotor region of the BACE-1 gene [53]. While BACE-1 cleavage of AβPP is the rate limiting step in amyloid-β production, hypoxia and ischemia also increases expression and activation of γ-secretase through multiple proposed mechanisms [52]. In addition to hypoxia enhancing the amyloidogenic pathway of AβPP processing, there is also evidence that it inhibits the non-amyloidogenic pathway.…”

“…The α-secretase activity is primarily due to two members of the disintegrin and metalloproteinase domain-containing protein (ADAM), ADAM10, and ADAM17. These proteins initiate the non-amyloidogenic pathway by cleaving AβPP within the amyloid-β domain resulting in the release of the soluble N-terminal ectodomain (sAβPPα) [52, 54]. In turn, sAβPPα has a number of effects including inhibition of BACE-1 [55].…”

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“…The hypoxic conditions are thought to increase the accumulation of Aβ peptides through the activation of BACE1 and γ-secretase [307]. Additionally, disruption of the blood–brain barrier has been suggested to impair clearance of Aβ peptides from the brain [48].…”

Hypoxia in CNS Pathologies: Emerging Role of miRNA-Based Neurotherapeutics and Yoga Based Alternative Therapies

“…Furthermore, hypoxia and ischemia activates processing of amyloid precursor protein and plays a crucial role in the pathogenesis of AD (Salminen et al, 2017). Several investigations using cellular models and in vivo studies have revealed that expression and activity of neprilysin (NEP), which is an Aβ-degrading enzyme, declines with age and also under hypoxic/ischemic conditions.…”