ABCA1 is Necessary for Bexarotene-Mediated Clearance of Soluble Amyloid Beta from the Hippocampus of APP/PS1 Mice

Corona, Angela W.; Kodoma, Nathan; Casali, Brad T.; Landreth, Gary E.

doi:10.1007/s11481-015-9627-8

Cited by 48 publications

(41 citation statements)

References 37 publications

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“…The brain cryopreservation was as described (Corona et al, 2016), except the whole brain was used, and sagittal sections (10 µm-thick, cut at 1.2–1.5 mm from the midline) were mounted on slides prior to staining. Plaque abundance was analyzed as described (Corona et al, 2016), separately with 1% aqueous ThioS and primary mouse 6E10 antibody (1:1,000; Covance).…”

Section: Methodsmentioning

confidence: 99%

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Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease

et al. 2017

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Cytochrome P450 46A1 (CYP46A1 or cholesterol 24-hydroxylase) controls cholesterol elimination from the brain and plays a role in higher order brain functions. Genetically enhanced CYP46A1 expression in mouse models of Alzheimer’s disease mitigates the manifestations of this disease. We enhanced CYP46A1 activity pharmacologically by treating 5XFAD mice, a model of rapid amyloidogenesis, with a low dose of the anti-HIV medication efavirenz. Efavirenz was administered from 1 to 9 months of age, and mice were evaluated at specific time points. At one month of age, cholesterol homeostasis was already disturbed in the brain of 5XFAD mice. Nevertheless, efavirenz activated CYP46A1 and mouse cerebral cholesterol turnover during the first four months of administration. This treatment time also reduced amyloid burden and microglia activation in the cortex and subiculum of 5XFAD mice as well as protein levels of amyloid precursor protein and the expression of several genes involved in inflammatory response. However, mouse short-term memory and long-term spatial memory were impaired, whereas learning in the context-dependent fear test was improved. Additional four months of drug administration (a total of eight months of treatment) improved long-term spatial memory in the treated as compared to the untreated mice, further decreased amyloid-β content in 5XFAD brain, and also decreased the mortality rate among male mice. We propose a mechanistic model unifying the observed efavirenz effects. We suggest that CYP46A1 activation by efavirenz could be a new anti-Alzheimer’s disease treatment and a tool to study and identify normal and pathological brain processes affected by cholesterol maintenance.

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Section: Methodsmentioning

confidence: 99%

“…Plaque abundance was analyzed as described (Corona et al, 2016), separately with 1% aqueous ThioS and primary mouse 6E10 antibody (1:1,000; Covance). For the latter, the antigen retrieval was in 88% aqueous formic acid solution for 3 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease

et al. 2017

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“…In the APP/PS1 mouse model of AD, genistein (PPARγ agonist) and bexarotene (RXR agonist which crosses the blood-brain barrier) treatments lowered plaque load and Aβ levels due to increased apoE release from astrocytes, together with a reduction of microgliosis (Bonet-Costa et al, 2016). The decrease in Aβ by bexarotene treatment is dependent on ABCA1’s lipidation of apoE (Corona et al, 2016). Bexarotene also increases the expression of genes involved in microglial Aβ phagocytosis, including Trem2, Tyrobp, Apoe, and Mertk (Lefterov et al, 2015).…”

Section: The Endocytic Pathway In Phagocytic Cellsmentioning

confidence: 99%

The endocytic pathway in microglia during health, aging and Alzheimer’s disease

Solé-Domènech

Cruz

Capetillo-Zárate

et al. 2016

Ageing Research Reviews

105

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Microglia, the main phagocytes of the central nervous system (CNS), are involved in the surveillance and maintenance of nervous tissue. During normal tissue homeostasis, microglia migrate within the CNS, phagocytose dead cells and tissue debris, and modulate synapse pruning and spine formation via controlled phagocytosis. In the event of an invasion by a foreign body, microglia are able to phagocytose the invading pathogen and process it proteolytically for antigen presentation. Internalized substrates are incorporated and sorted within the endocytic pathway and thereafter transported via complex vesicular routes. When targeted for degradation, substrates are delivered to acidic late endosomes and lysosomes. In these, the enzymatic degradation relies on pH and enzyme content. Endocytosis, sorting, transport, compartment acidification and degradation are regulated by complex signaling mechanisms, and these may be altered during aging and pathology. In this review, we discuss the endocytic pathway in microglia, with insight into the mechanisms controlling lysosomal biogenesis and pH regulation. We also discuss microglial lysosome function associated with Alzheimer’s disease (AD) and the mechanisms of amyloid-beta (Aβ) internalization and degradation. Finally, we explore some therapies currently being investigated to treat AD and their effects on microglial response to Aβ, with insight in those involving enhancement of lysosomal function.

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“…Treatment of AD mouse models with LXR agonists reduces Aβ levels and improves cognition [103–105]. Treatment with the RXR agonist bexarotene also improves Aβ clearance and cognition [106], in a manner dependent on the presence of both APOE [106] and ABCA1 [107]. Other treatments to improve apoE4 lipidation (e.g., microRNA-33 induction [108], retinoic acid [109]) could prove useful in preventing brain phenotypes associated with APOE4 and neurodegeneration.…”

Section: Mechanisms Of Effects Of Apoe Genotype Effectsmentioning

confidence: 99%

Alzheimer's Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function

Battista¹,

Heinsinger²,

Rebeck³

2016

CAR

105

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APOE-ε4 is the strongest genetic risk factor for Alzheimer’s disease (AD), and is associated with an increase in the levels of amyloid deposition and an early age of onset. Recent data demonstrate that AD pathological changes occur decades before clinical symptoms, raising questions about the precise onset of the disease. Now a convergence of approaches in mice and humans has demonstrated that APOE-ε4 affects normal brain function even very early in life in the absence of gross AD pathological changes. Normal mice expressing APOE4 have task-specific spatial learning deficits, as well as reduced NMDAR-dependent signaling and structural changes to presynaptic and postsynaptic compartments in neurons, particularly in hippocampal regions. Young humans possessing APOE-ε4 are more adept than APOE-ε4 negative individuals at some behavioral tasks, and functional magnetic resonance imaging has shown that inheritance of APOE-ε4 has specific effects on medial temporal brain activities. These findings suggest that inheritance of APOE-ε4 causes life long changes to the brain that may be related to the late risk of AD. Several possible mechanisms of how APOE-ε4 could affect brain neurochemistry, structure, and function are reviewed.

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ABCA1 is Necessary for Bexarotene-Mediated Clearance of Soluble Amyloid Beta from the Hippocampus of APP/PS1 Mice

Cited by 48 publications

References 37 publications

Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease

Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease

The endocytic pathway in microglia during health, aging and Alzheimer’s disease

Alzheimer's Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function

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