Energy Inhibition Elevates β-Secretase Levels and Activity and Is Potentially Amyloidogenic in APP Transgenic Mice: Possible Early Events in Alzheimer's Disease Pathogenesis
Open accessAbstract
β-Secretase [β-site amyloid precursor protein-cleaving enzyme 1 (BACE1)] is the key rate-limiting enzyme for the production of the β-amyloid (Aβ) peptide involved in the pathogenesis of Alzheimer's disease (AD). BACE1 levels and activity are increased in AD brain and are likely to drive Aβ 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 ∼150% 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 APPsβ were also elevated and paralleled the BACE1 increase in both relative amount and duration. Importantly, cerebral Aβ40 levels in Tg2576 were increased to ∼200% 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 Aβ overproduction. This process may represent one of the earliest pathogenic events in AD.
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Nitro-oxidative modifications to mitochondrial proteins are associated with pathological changes in mitochondrial redox state, morphology, and bioenergetics in preclinical and early AD patients.
“Nitro-oxidative modifications to mitochondrial proteins are associated with pathological changes in mitochondrial redox state, morphology, and bioenergetics in preclinical and early AD patients”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Velliquette et al., 2005
The Introduction and ‘Potential mechanisms underlying the persistent BACE1 increase’ section (page unavailable) report reduced brain glucose metabolism in preclinical and clinical AD, supporting the claim’s broad point about impaired bioenergetics. They do not report nitro-oxidative modifications to mitochondrial proteins or associate those modifications with mitochondrial redox state, morphology, or bioenergetics in patients. (LLM, conf=0.82)
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- Authors
- Velliquette, R. A., O'Connor, T., & Vassar, R.
- Affiliations
- Northwestern University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-11-23
- Volume
- 25
- Issue
- 47
- Pages
- 10874-10883
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725876
- OpenAlex
- W2094185290
- Cited by
- 254
- References
- 10
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 8 · 2022: 12 · 2021: 11 · 2020: 10 · 2019: 9 · 2018: 11 · 2017: 7 · 2016: 14 · 2015: 10 · 2014: 20 · 2013: 11 · 2012: 24
- FWCI
- 8.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Northwestern University
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- beta-secretase, BACE1, Alzheimer's disease, brain glucose metabolism, amyloid-beta, APP transgenic mice, Tg2576 mice, 2-deoxyglucose, 3-nitropropionic acid, kainic acid, insulin, amyloidogenesis, preclinical Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Animals, Brain, Energy Metabolism, Humans, Mice, Inbred C57BL, Mice, Transgenic, Peptide Fragments, Endopeptidases, Time Factors, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Mice, Amyloid Precursor Protein Secretases
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