Mitochondrial respiratory inhibition and oxidative stress elevate β-secretase (BACE1) proteins and activity in vivo in the rat retina

Abstract

Cerebral hypometabolism, oxidative stress and beta-amyloid peptide (Abeta) accumulation are key pathological events in Alzheimer's disease (AD). Beta-secretase (BACE, i.e., BACE1), a prerequisite for Abeta genesis, is elevated in sporadic AD. Recent studies show BACE upregulation in experimental conditions likely associated with energy insufficiency and/or oxidative stress. We investigated the effect of sublethal doses of mitochondrial respiratory inhibitors and potential endogenous oxidative substances on BACE expression in vivo using the retina as a model. Retinas were analyzed biochemically and anatomically 48 h following intraocular applications of mitochondrial complex I, II and IV inhibitors including rotenone, 3-nitropropionic acid and sodium azide, and plaque-containing oxidants including Fe(3+) and Abeta42 fibrils (Abeta42f). All agents caused elevations of BACE proteins and beta-site amyloid precursor protein (APP) cleavage product, beta-CTF, in retinal lysates in a dose-dependant manner. BACE activity and Abeta40 levels were also increased in agent-treated retinas relative to vehicle controls. BACE immunoreactivity in normal adult rat retina was present mostly in the plexiform layers, indicating a localization of the enzyme to synaptic terminals. No apparent change in laminar or cellular distribution of BACE labeling was detected in the experimental retinas. However, signs of neuronal stress including glial activation were observed in agent-treated retinas especially in high dosage groups. Our data suggest that mitochondrial respiratory inhibition and oxidative stress facilitate BACE expression in vivo. In addition, plaque constituents such as Fe(3+) and Abeta42f may participate in a self-enforcing cycle of amyloidogenesis via BACE upregulation.

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

“…Multiple mechanisms are recently proposed to mediate the upregulation of BACE1 associated with AD. Those include the increased phosphorylation of the translation initiation factor eIF2a Devi and Ohno, 2010b;O'Connor et al, 2008), caspase-3-dependent inactivation of GGA3 leading to decreased lysosomal degradation of BACE1 (Sarajarvi et al, 2009;Tesco et al, 2007), changes in microRNA expression profiles (Hebert et al, 2008;Wang et al, 2008), p25/cyclin-dependent kinase 5 pathways (Cruz et al, 2006;Wen et al, 2008), calpain activation (Liang et al, 2010), the receptor for advanced glycation end products (RAGE) (Cho et al, 2009;Guglielmotto et al, 2010), and oxidative stress or related signals such as nuclear factor-kB, c-Jun N-terminal kinase, and p38 MAPK (Chen et al, 2011;Chen et al, 2008;Coma et al, 2008;Xiong et al, 2007). Further study will be needed to determine the molecular pathways by which activation of BDNF-TrkB signaling may counteract the BACE1 elevation in 5XFAD mice.…”

Linking vascular disorders and Alzheimer's disease: Potential involvement of BACE1

“…Indeed, young adults carrying the ApoE4 allele, and MCI patients, exhibit reduced brain glucose metabolism (Reiman et al, 1996;Small et al, 2000;Mosconi et al, 2004;Mosconi, 2005), indicating that impaired energy metabolism may be an early contributing event to AD pathology rather than a consequence of the disease process. Importantly, several key down-stream cellular consequences of vascular insults and the resulting CBH, such as hypoxia, energy depletion and cellular stress have been linked with an elevation in BACE1 levels and activity (Tamagno et al, 2002(Tamagno et al, , 2005Tong et al, 2005;Velliquette et al, 2005;Sun et al, 2006;Xiong et al, 2007;Yan et al, 2007). Thus, in addition to potential elevations in Aβ occurring as a consequence of its own vasoactive properties, as detailed above, it appears possible that cardio-and cerebrovascular insults could elevate Aβ levels via a mechanism involving BACE1 elevation.…”

“…Given the apparent importance of metabolic dysfunction and amyloidosis in AD, it is noteworthy that BACE1 upregulation has been observed under various experimental conditions likely involving energy disruption and/or mitochondrial stress (Tong et al, 2005;Velliquette et al, 2005;Sun et al, 2006;Tesco et al, 2007;Xiong et al, 2007). Indeed, elevated BACE1 levels and activity have been reported in vitro (Tamagno et al, 2002(Tamagno et al, , 2005Tong et al, 2005) and in vivo (Velliquette et al, 2005;Xiong et al, 2007) under conditions of altered energy metabolism and oxidative stress.…”

The Mitochondrial Secret(ase) of Alzheimer's Disease

“…First, increased BACE protein levels and activity in postmortem AD brain [54,162] are linked to increased γ-secretase cleavage of AβPP [163] and correlate with oxidative stress levels [164]. Endogenously and exogenously-induced ROS overproduction increases both BACE1 and PS1 expression and activity [165][166][167][168], which are mediated through the activation of the JNK pathway [169][170][171] and results in increased Aβ production [161,172]. In addition, Jo and colleagues report γ-secretase is responsible for ROS-induced increases in β-secretase activity, since pharmacological or genetic loss of γ-secretase function ameliorates an increase in β-secretase [173].…”