Bexarotene reduces network excitability in models of Alzheimer's disease and epilepsy

Bomben, Valerie C.; Holth, Jerrah K.; Reed, J. Graham; Cramer, Paige E.; Landreth, Gary E.; Noebels, Jeffrey L.

doi:10.1016/j.neurobiolaging.2014.03.029

Cited by 58 publications

(36 citation statements)

References 20 publications

(24 reference statements)

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“…APOE4 TR mice show an increased risk of seizures and synchronous hippocampal neurons firing, as well as a greater sensitivity to treatment with a drug to induce seizures [120]. Treatment with an RXR agonist reduced epileptiform spiking seen in mouse models of AD and epilepsy unrelated to APOE genotype [121]. Aged female APOE4 mice have fewer interneurons in the hippocampal hilus [37], also altering the excitability of the dentate gyrus.…”

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

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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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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

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“…These two proteins have been functionally linked to phosphatidylinositol-binding clathrin assembly protein (PICALM) [17], which is identified as a genetic risk factor for AD [18,19]. Therefore, increasing the clearance of Aβ across the BBB via the induction of P-gp or/and LRP1 expression, and consequently PICALM, may be an effective strategy to protect the brain from the accumulation of Aβ [20] and prevent AD onset. One of the new AD treatments currently under development is the ketogenic diet (KD) [21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Ketone Bodies Promote Amyloid-β1–40 Clearance in a Human in Vitro Blood–Brain Barrier Model

Versele

Corsi

Fuso

et al. 2020

IJMS

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Alzheimer’s disease (AD) is characterized by the abnormal accumulation of amyloid-β (Aβ) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport of Aβ across the blood–brain barrier (BBB) appears to be integral to disease development. At present, no effective therapeutic treatment against AD exists, and the adoption of a ketogenic diet (KD) or ketone body (KB) supplements have been investigated as potential new therapeutic approaches. Despite experimental evidence supporting the hypothesis that KBs reduce the Aβ load in the AD brain, little information is available about the effect of KBs on BBB and their effect on Aβ transport. Therefore, we used a human in vitro BBB model, brain-like endothelial cells (BLECs), to investigate the effect of KBs on the BBB and on Aβ transport. Our results show that KBs do not modify BBB integrity and do not cause toxicity to BLECs. Furthermore, the presence of KBs in the culture media was combined with higher MCT1 and GLUT1 protein levels in BLECs. In addition, KBs significantly enhanced the protein levels of LRP1, P-gp, and PICALM, described to be involved in Aβ clearance. Finally, the combined use of KBs promotes Aβ efflux across the BBB. Inhibition experiments demonstrated the involvement of LRP1 and P-gp in the efflux. This work provides evidence that KBs promote Aβ clearance from the brain to blood in addition to exciting perspectives for studying the use of KBs in therapeutic approaches.

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“…551 Bomben and co-workers [43] suggest that the neuro-552 protective action of BEXA might be A␤-independent, 553 since they noted that it could reduce network hyperex-554 citability in J20 AD mice and in other hyperexcitability 555 models such as the Kv1.1 null mouse which has a 556 pronounced epileptic phenotype [44]. 557 It has also been proposed that BEXA, because of its …”

mentioning

confidence: 99%

The Continuing Failure of Bexarotene in Alzheimer’s Disease Mice

Balducci

Paladini

Micotti

et al. 2015

JAD

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Alzheimer's disease (AD) is the most common form of dementia characterized by synaptic dysfunction, memory loss, neuroinflammation, and neuronal cell death. Amyloid-β (Aβ), recognized as the main culprit of AD, aggregates and accumulates in the extracellular compartment as neuritic plaques, after deregulation of its production or clearance. Apolipoprotein E (ApoE) plays a major role in Aβ clearance and its expression is transcriptionally regulated by the liver X receptor and retinoid X receptors (RXRs) system. Bexarotene (BEXA), an RXR agonist that increases ApoE expression and microglia phagocytosis has been proposed as a promising therapy for AD, resolving both the amyloid pathology and memory loss. Despite the first compelling report, however, multiple failures have been documented, raising concern about whether BEXA could in fact become a novel disease-modifying strategy for AD. To help clarify this, we investigated the effect of BEXA in vivo at multiple levels in TASTPM transgenic mice. Seven-day oral administration of BEXA to these mice did not achieve any significant memory improvement, plaque reduction, or enhancement of microglial cell activation. No differences were found when specifically investigating the microglial phagocytic state in vivo. In addition, a brain structural analysis with magnetic resonance did not detect any BEXA-mediated change in the volume reduction of the main affected brain areas in our mice. These results suggest that BEXA has no beneficial effects on the multi-factorial pathologic phenotype of AD mice.

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Bexarotene reduces network excitability in models of Alzheimer's disease and epilepsy

Cited by 58 publications

References 20 publications

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

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

Ketone Bodies Promote Amyloid-β1–40 Clearance in a Human in Vitro Blood–Brain Barrier Model

The Continuing Failure of Bexarotene in Alzheimer’s Disease Mice

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