β-Amyloid Inhibits Protein Prenylation and Induces Cholesterol Sequestration by Impairing SREBP-2 Cleavage

Mohamed, Ahmed F.; Saavedra, Lucila; Pardo, Alba Di; Sipione, Simonetta; Chaves, E

doi:10.1523/jneurosci.0630-12.2012

Cited by 38 publications

(37 citation statements)

References 84 publications

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“…In cell culture, amyloid-β 1–40 peptide was found to inhibit cholesterol biosynthesis by inhibiting HMGCR, the rate-limiting enzyme in the production of cholesterol (Grimm et al, 2005). Also in cell culture, amyloid-β 1–42 was demonstrated to reduce the levels of mature SREBP-2 and affect cholesterol biosynthesis (Mohamed et al, 2012). It is conceivable that these and probably other processes (Grosgen et al, 2010) can further disturb cholesterol maintenance in the 5XFAD brain, which is already compromised prenatally by the transgene expression.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Aβ and AICD, have been demonstrated to modulate lipid homeostasis (Grimm et al, 2012). In particular, γ‐secretase processing of APP has been reported to decrease cholesterol synthesis via inhibition of HMGCR activity and Aβ to impair SREBP2 processing (Grimm et al, 2005; Mohamed et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein controls cholesterol turnover needed for neuronal activity

et al. 2013

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Perturbation of lipid metabolism favours progression of Alzheimer disease, in which processing of Amyloid Precursor Protein (APP) has important implications. APP cleavage is tightly regulated by cholesterol and APP fragments regulate lipid homeostasis. Here, we investigated whether up or down regulation of full-length APP expression affected neuronal lipid metabolism. Expression of APP decreased HMG-CoA reductase (HMGCR)-mediated cholesterol biosynthesis and SREBP mRNA levels, while its down regulation had opposite effects. APP and SREBP1 co-immunoprecipitated and co-localized in the Golgi. This interaction prevented Site-2 protease-mediated processing of SREBP1, leading to inhibition of transcription of its target genes. A GXXXG motif in APP sequence was critical for regulation of HMGCR expression. In astrocytes, APP and SREBP1 did not interact nor did APP affect cholesterol biosynthesis. Neuronal expression of APP decreased both HMGCR and cholesterol 24-hydroxylase mRNA levels and consequently cholesterol turnover, leading to inhibition of neuronal activity, which was rescued by geranylgeraniol, generated in the mevalonate pathway, in both APP expressing and mevastatin treated neurons. We conclude that APP controls cholesterol turnover needed for neuronal activity.

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“…It is well-known that Rab and Rho proteins require prenylation for membrane association and for binding to GDIs. GDIs hold prenylated proteins in the cytosol, acting not only as passive regulators of GTPase activity but also preventing their degradation (Boulter and Garcia-Mata, 2010;Mohamed et al, 2012). GDI capture of membrane-bound Rabs could be physically prevented by modifications in the cholesterol content within the membranes (Ganley and Pfeffer, 2006).…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Treatment Highlights a New Role for the Isoprenoid/Cholesterol Biosynthetic Pathway in the Modulation of Emotional Reactivity and Cognitive Performance in Rats

Segatto¹,

Manduca²,

Lecis³

et al. 2013

Neuropsychopharmacol

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The aim of the present work was to shed light on the role played by the isoprenoid/cholesterol biosynthetic pathway in the modulation of emotional reactivity and memory consolidation in rodents through the inhibition of the key and rate-limiting enzyme 3-hydroxy 3-methylglutaryl Coenzyme A reductase (HMGR) both in vivo and in vitro with simvastatin. Three-month-old male Wistar rats treated for 21 days with simvastatin or vehicle were tested in the social interaction, elevated plus-maze, and inhibitory avoidance tasks; after behavioral testing, the amygdala, hippocampus, prefrontal cortex, dorsal, and ventral striatum were dissected out for biochemical assays. In order to delve deeper into the molecular mechanisms underlying the observed effects, primary rat hippocampal neurons were used. Our results show that HMGR inhibition by simvastatin induces anxiogenic-like effects in the social interaction but not in the elevated plusmaze test, and improves memory consolidation in the inhibitory avoidance task. These effects are accompanied by imbalances in the activity of specific prenylated proteins, Rab3 and RhoA, involved in neurotransmitter release, and synaptic plasticity, respectively. Taken together, the present findings indicate that the isoprenoid/cholesterol biosynthetic pathway is critically involved in the physiological modulation of both emotional and cognitive processes in rodents.

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β-Amyloid Inhibits Protein Prenylation and Induces Cholesterol Sequestration by Impairing SREBP-2 Cleavage

Abstract: Accumulation of ␤-amyloid (A␤) inside brain neurons is an early and crucial event in Alzheimer's disease (AD). Studies in brains of

Cited by 38 publications

References 84 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

Amyloid precursor protein controls cholesterol turnover needed for neuronal activity

Simvastatin Treatment Highlights a New Role for the Isoprenoid/Cholesterol Biosynthetic Pathway in the Modulation of Emotional Reactivity and Cognitive Performance in Rats

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