Upregulation of BACE1 and β-Amyloid Protein Mediated by Chronic Cerebral Hypoperfusion Contributes to Cognitive Impairment and Pathogenesis of Alzheimer’s Disease

Abstract

Chronic cerebral hypoperfusion (CCH) increases the risk of Alzheimer disease (AD) through several biologically plausible pathways, but the relationship between CCH and the development of AD remains uncertain. To investigate expression of APP, BACE1 and A beta in the hippocampus of BCCAO rats and study pathophysiological mechanism of AD from CCH. CCH rat model was established by chronic bilateral common carotid artery occlusion (BCCAO). Behavior was evaluated after BCCAO with Morris water maze and open-field task. Expression of A beta was measured by enzyme linked immunosorbent assay (ELISA). beta-Amyloid precursor protein cleavage enzyme 1 (BACE1) and beta-amyloid precursor protein (APP) were tested by ELISA, Western blotting and RT-PCR. Cognitive impairment occurred with CCH by Morris water maze test and open-field task. The BACE1 and A beta level in BCCAO rats was more increased than sham-operation control rats (P < 0.01) but APP had no difference(P > 0.05). The expression of BACE1 and A beta has no inter-group difference in BCCAO rats (P > 0.05). The level of BACE1 and A beta had positive correlation with cognitive impairment (P < 0.01) while no correlation was observed between APP and cognitive impairment. Chronic cerebral ischemia contributes to cognitive impairment and vascular pathogenesis of Alzheimer's disease that chronic cerebral hypoperfusion increases BACE1 and A beta level in brain.

Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer’s disease (Review)

“…C99 is then further cleaved by γ-secretase within the hydrophobic transmembrane domain at either Val711 or Ile713, finally releasing Aβ and the intracellular domain of APP. The non-amyloidogenic pathway, in which APP is sequentially cleaved by α-and γ-secretase, may prevent the production of Aβ (116,117). Several studies have reported that propargylamine-containing compounds, including ladostigil and M30, irreversible and selective MAO-B inhibitors, act as modulators of the proteolytic cleavage of APP via activation of the p42/44MAPK and PKC signaling pathways (61,(118)(119)(120).…”

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

“…White matter damage is detectable with diffusion tensor imaging (DTI) at the early stages of brain injury following CCH (Wang et al, 2015). In addition, cerebral hypoperfusion accelerates cerebral amyloid angiopathy (Okamoto et al, 2012), enhances tau hyperphosphorylation, upregulates β-amyloid precursor protein cleavage enzyme 1 (BACE1) and β-amyloid level in the brain (Zhiyou et al, 2009), the main neuropathological hallmarks of AD.…”

RAGE Inhibition in Microglia Prevents Ischemia-Dependent Synaptic Dysfunction in an Amyloid-Enriched Environment

“…Indeed, hypoxia modulates the expression and activity of A␤-metabolizing enzymes, resulting in increased A␤ peptides, including the deleterious A␤(1-42) (Sun et al, 2006;Guglielmotto et al, 2009;Pluta et al, 2013). Moreover, an increased susceptibility to ischemia has been shown in the brains of amyloid precursor protein (APP)-overexpressing mice (Zhang et al, 1997). However, a causal relationship between AD and brain ischemia at the molecular and functional level has not been established.…”

“…Interestingly, RAGE (Receptor for Advanced Glycation Endproducts) expression changes in neuronal and non-neuronal cells under ischemic conditions (Pichiule et al, 2007;Zhai et al, 2008) and AD (Yan et al, 1996). RAGE is a receptor mediating and focusing A␤ effects on neuronal and non-neuronal cells (Yan et al, 1995;Deane et al, 2003), contributing to A␤-dependent functional impairment in hippocampus and entorhinal cortex (EC; Origlia et al, 2008Origlia et al, , 2010.…”