CYP46A1 Activation by Efavirenz Leads to Behavioral Improvement without Significant Changes in Amyloid Plaque Load in the Brain of 5XFAD Mice
Open accessAbstract
Efavirenz, the FDA-approved anti-retroviral medication, is evaluated in the clinical trial in patients with mild cognitive impairment or early dementia due to Alzheimer's disease. Efavirenz is assessed for activation of cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme that converts cholesterol to 24-hydroxycholesterol. Cholesterol 24-hydroxylation is the major pathway for brain cholesterol removal, and a mechanism that controls brain cholesterol turnover. The present study tested efavirenz on 5XFAD mice (an Alzheimer's model) at a very low daily dose of 0.1 mg/kg body weight. Efavirenz treatment started from three months of age, after amyloid plague appearance, and continued for 6 months. This treatment led to CYP46A1 activation in the brain, enhancement of brain cholesterol turnover, behavioral improvements, reduction in microglia activation but increased astrocyte reactivity. The levels of the soluble and insoluble amyloid 40 and 42 peptides were unchanged while the number and area of the dense core amyloid plaques were slightly decreased. The measurements of the brain levels of several pre- and post-synaptic proteins (Munc13-1, PSD-95, gephyrin, synaptophysin, synapsin-1, and calbindin-D28k) suggested efavirenz effect at the synaptic level. Efavirenz treatment in the present work seems to represent a model of behavioral and other improvements independent of the levels of the amyloid peptides and provides insight into potential outcomes of the future clinical trial.
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There are many examples of environmental and/or microglial gene manipulation in mouse models of amyloidosis in which cognition improved in the absence of a decrease, or even in the presence of an increase, in plaques.
“there are many examples of environmental and/or microglial gene manipulation in mouse models of amyloidosis in which cognition improved in the absence of a decrease, or even in the presence of an increase, in plaques.61,62”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [62]
The Discussion (page unavailable) reports improved performance in hippocampus-dependent behavioral tests after efavirenz treatment of 5XFAD mice, without significant changes in Aβ peptide levels. The Amyloid Pathology section (page unavailable) reports no apparent decrease in 6E10 staining, but a small, significant decrease in dense-core plaque staining. This is an example of improvement without a substantial plaque reduction, but the intervention was drug treatment, not environmental or microglial gene manipulation, and the paper does not report increased plaques. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe inability to associate altered pathology with detectable changes in brain function may be a result of the focus on the earliest stages of pathology and/or a dissociation between plaque load and function.
“which may be a result of our focus on the earliest stages of pathology and/or a dissociation between plaque load and function, which has been observed in other settings.21,60,62”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [62]
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References 97 · Cited by 86
Research works printed but not linked: 2
- Hoeffer CA, Klann E 2009 NMDA Receptors and Translational Control. In Biology of the NMDA Receptor. A. M. Van Dongen, editor. CRC Press/Taylor & Francis. Taylor & Francis Group, LLC., Boca Raton (FL), 103-121
- Ovsepian SV, O'Leary VB, Zaborszky L, et al (2018). Amyloid Plaques of Alzheimer's Disease as Hotspots of Glutamatergic Activity. Neuroscientist: in press 84. Varoqueaux F, Sigler A, Rhee JS, et al (2002). Total arrest of spon- taneous and evoked synaptic transmission but normal synaptogen- esis in the absence of Munc13-mediated vesicle priming. Proc Natl Acad Sci U S A 99: 9037-9042
- Authors
- Petrov, A. M., Lam, M., Mast, N., Moon, J., Li, Y., Maxfield, E., & Pikuleva, I. A.
- Affiliations
- Case Western Reserve University (US)
- Corresponding author
- Pikuleva, Irina A.
- Venue
- Neurotherapeutics
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 16
- Issue
- 3
- Pages
- 710-724
- ISSN
- 1878-7479 (ISSN-L)
- PMC
- PMC6694340
- OpenAlex
- W2944738928
- Cited by
- 86
- References
- 97
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 16 · 2023: 14 · 2022: 18 · 2021: 14 · 2020: 7 · 2019: 5
- FWCI
- 7.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neurotherapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM062882)
- National Eye Institute (EY11373)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- efavirenz, CYP46A1, 24S-hydroxycholesterol, Alzheimer's disease, 5xFAD mice, amyloid plaques, microglial activation, astrocyte activation, synaptic proteins, behavior improvement
- MeSH terms
- Cholesterol 24-Hydroxylase, Alkynes, Alzheimer Disease, Animals, Brain, Conditioning, Classical, Cyclopropanes, Disease Models, Animal, Enzyme Activation, Female, Male, Nootropic Agents, Maze Learning, Benzoxazines, Mice, Plaque, Amyloid
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