CYP46A1 Activation by Efavirenz Leads to Behavioral Improvement without Significant Changes in Amyloid Plaque Load in the Brain of 5XFAD Mice

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.

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

“…The brain-specific, cholesterol-catabolic enzyme CH24H has gained increased attention as a potential drug target 18,19 . Clarifying hitherto unproven therapeutic benefits of CH24H inhibitor 26 , the present study provides new insights into the therapeutic relevance of pharmacological modulation of this enzyme [18][19][20]42 . The data shown here suggest that 24S-hydroxycholesterol lowering by soticlestat has therapeutic potential in diseases with underlying excitatory/inhibitory imbalance in the brain.…”

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

“…Light and dark magenta bars indicate relative protein levels in Cntr and Tx mice from the 2TP, which is shown for comparison. Data for the 2TP from (38). The results are presented as means 6 SD of measurements in individual mice.…”

“…Asterisks are significant changes relative to the corresponding control mice as assessed by a 2-tailed, unpaired Student's t test. *P # 0.05, **P # 0.01. measured in 9-mo-old mice from the 2TP (38). EFV treatment did not affect protein expression of protein Unc-13 homolog A (Munc13-1; a presynaptic component) (43) and calbindin (a neuron-specific Ca 2+ buffering protein) (44) but increased the expression of PSD-95 (a postsynaptic scaffold protein in excitatory/glutamatergic synapses) (45), gephyrin (a postsynaptic scaffold protein in inhibitory synapses) (46), synaptophysin (the most abundant protein in synaptic vesicles) (47), and synapsin-1 (one of the main anchor protein connecting synaptic vesicles in vesicular pools) (48).…”

“…Different effects on behavioral performance were attributed to the brain cholesterol depletion during the first 3 mo of drug dosing when EFV was administered to young mice whose brains and a pool of brain cholesterol were still expanding (36). In the second treatment paradigm (2TP), EFV was given to mice from 3 to 9 mo of age, and animals were only evaluated at the end of treatment (i.e., at the age of 9 mo) (38). The overall Ab burden in EFV-treated 5XFAD mice remained unchanged; nevertheless, behavioral performance was improved (38).…”

“…In the second treatment paradigm (2TP), EFV was given to mice from 3 to 9 mo of age, and animals were only evaluated at the end of treatment (i.e., at the age of 9 mo) (38). The overall Ab burden in EFV-treated 5XFAD mice remained unchanged; nevertheless, behavioral performance was improved (38). Herein, we conducted additional characterizations of 9-mo-old 5XFAD mice from the Figure 1.…”