Energy Inhibition Elevates β-Secretase Levels and Activity and Is Potentially Amyloidogenic in APP Transgenic Mice: Possible Early Events in Alzheimer's Disease Pathogenesis

Abstract

␤-Secretase [␤-site amyloid precursor protein-cleaving enzyme 1 (BACE1)] is the key rate-limiting enzyme for the production of the ␤-amyloid (A␤) peptide involved in the pathogenesis of Alzheimer's disease (AD). BACE1 levels and activity are increased in AD brain and are likely to drive A␤ overproduction, but the cause of BACE1 elevation in AD is unknown. Interestingly, cerebral glucose metabolism and blood flow are both reduced in preclinical AD, suggesting that impaired energy production may be an early pathologic event in AD. To determine whether reduced energy metabolism would cause BACE1 elevation, we used pharmacological agents (insulin, 2-deoxyglucose, 3-nitropropionic acid, and kainic acid) to induce acute energy inhibition in C57/B6 wild-type and amyloid precursor protein (APP) transgenic (Tg2576) mice. Four hours after treatment, we observed that reduced energy production caused a ϳ150% increase of cerebral BACE1 levels compared with control. Although this was a modest increase, the effect was long-lasting, because levels of the BACE1 enzyme remained elevated for at least 7 d after a single dose of energy inhibitor. In Tg2576 mice, levels of the BACE1-cleaved APP ectodomain APPs␤ were also elevated and paralleled the BACE1 increase in both relative amount and duration. Importantly, cerebral A␤40 levels in Tg2576 were increased to ϳ200% of control at 7 d after injection, demonstrating that energy inhibition was potentially amyloidogenic. These results support the hypothesis that impaired energy production in the brain may drive AD pathogenesis by elevating BACE1 levels and activity, which, in turn, lead to A␤ overproduction. This process may represent one of the earliest pathogenic events in AD.

Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase

“…Thus, using a pharmacological model of energy metabolism inhibition in Tg2576 mice, Velliquette et al . reported that Aβ levels were significantly increased suggesting for the first time that energy deprivation acts as an amyloidogenic stimulus in vivo (Velliquette et al ., 2005). In a later paper that used glucose deprivation in cell culture as a model of energy deficiency, it was demonstrated a post‐transcriptional increase in BACE1 level and enhanced Aβ production (O'Connor et al ., 2008).…”

Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment

“…The pathologies may simply induce catalytic changes in the enzymes, an idea supported by energy metabolism changes in transgenic mouse models of AD (Dodart et al, 1999;Reiman et al, 2000;Strazielle et al, 2003;Reddy et al, 2004;Caspersen et al, 2005;Valla et al, 2006). Conversely, energy inhibition can alter APP processing in cultured cells (Gabuzda et al, 1994), in mouse models of amyloid overexpression, increasing β-secretase activity and amyloidogenicity (Velliquette et al, 2005), and in rats, exacerbating Aβ peptide toxicity, particularly in synapses (Arias et al, 2002). Also, mitochondrial involvement in AD etiology is supported by studies using a cybrid cell model, which utilizes mtDNA-depleted cultured cells re-populated with AD patient or control mitochondria.…”

Ketone Bodies as a Therapeutic for Alzheimer's Disease

“…Furthermore, it was found that such treatments led to a 2-fold increase in A␤40 levels 7 days after treatment. 25 An alternative hypothesis is that both low CMRglc and altered processing of App are symptoms of a more general disturbance. One possible culprit is alteration in lipid/glucose metabolism induced either by some environmental factor, such as diet, or by genetic predisposition, such as possession of an APOE4 allele, or both.…”