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1.
Acta Neuropathol Commun ; 9(1): 58, 2021 04 01.
Article in English | MEDLINE | ID: mdl-33795005

ABSTRACT

Prion diseases are fatal, infectious, and incurable neurodegenerative disorders caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform (PrPSc). In humans, there are sporadic, genetic and infectious etiologies, with sporadic Creutzfeldt-Jakob disease (sCJD) being the most common form. Currently, no treatment is available for prion diseases. Cellular cholesterol is known to impact prion conversion, which in turn results in an accumulation of cholesterol in prion-infected neurons. The major elimination of brain cholesterol is achieved by the brain specific enzyme, cholesterol 24-hydroxylase (CYP46A1). Cyp46A1 converts cholesterol into 24(S)-hydroxycholesterol, a membrane-permeable molecule that exits the brain. We have demonstrated for the first time that Cyp46A1 levels are reduced in the brains of prion-infected mice at advanced disease stage, in prion-infected neuronal cells and in post-mortem brains of sCJD patients. We have employed the Cyp46A1 activator efavirenz (EFV) for treatment of prion-infected neuronal cells and mice. EFV is an FDA approved anti-HIV medication effectively crossing the blood brain barrier and has been used for decades to chronically treat HIV patients. EFV significantly mitigated PrPSc propagation in prion-infected cells while preserving physiological PrPC and lipid raft integrity. Notably, oral administration of EFV treatment chronically at very low dosage starting weeks to months after intracerebral prion inoculation of mice significantly prolonged the lifespan of animals. In summary, our results suggest that Cyp46A1 as a novel therapeutic target and that its activation through repurposing the anti-retroviral medication EFV might be valuable treatment approach for prion diseases.


Subject(s)
Alkynes/pharmacology , Benzoxazines/pharmacology , Cholesterol 24-Hydroxylase/metabolism , Creutzfeldt-Jakob Syndrome/metabolism , Cyclopropanes/pharmacology , Cytochrome P-450 Enzyme Inhibitors/pharmacology , PrPSc Proteins/drug effects , Administration, Oral , Animals , Cholesterol 24-Hydroxylase/drug effects , Drug Repositioning , Humans , Membrane Microdomains/metabolism , Mice , PrPC Proteins/drug effects , PrPC Proteins/metabolism , PrPSc Proteins/metabolism
2.
Neurotherapeutics ; 16(3): 710-724, 2019 07.
Article in English | MEDLINE | ID: mdl-31062296

ABSTRACT

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.


Subject(s)
Alzheimer Disease/drug therapy , Benzoxazines/therapeutic use , Brain/drug effects , Cholesterol 24-Hydroxylase/metabolism , Nootropic Agents/therapeutic use , Plaque, Amyloid/metabolism , Alkynes , Alzheimer Disease/metabolism , Animals , Brain/metabolism , Cholesterol 24-Hydroxylase/drug effects , Conditioning, Classical/drug effects , Cyclopropanes , Disease Models, Animal , Enzyme Activation/drug effects , Female , Male , Maze Learning/drug effects , Mice
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