Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer’s Disease

Bonet-Costa, Vicent; Herranz-Pérez, Vicente; Blanco-Gandía, M. Carmen; Mas-Bargues, Cristina; Inglés, Marta; García-Tárraga, Patricia; Rodrı́guez-Arias, Marta; Miñarro, José; Borrás, Consuelo; García‐Verdugo, José Manuel; Viña, José

doi:10.3233/jad-151020

Cited by 79 publications

(47 citation statements)

References 44 publications

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“…The activation of PPARγ and RXRs controls brain inflammation and alters the inflammatory state of microglia (Bernardo and Minghetti, 2006). 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).…”

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

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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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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

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“…It is present in tofu (soybean curd) and its consumption has shown promising results as a moderator of cognitive deficits in AD [8]. Indeed, substantial evidence suggests that Gen inhibits Aβ 25–35 -induced toxicity via regulation of many relevant signaling pathways [9–11] and by facilitation of Aβ clearance from the nervous system [12]. Conversely, another study showed that dietary Gen can lead to cognitive impairment [13].…”

Section: Introductionmentioning

confidence: 99%

Genistein protects against Aβ25–35 induced apoptosis of PC12 cells through JNK signaling and modulation of Bcl-2 family messengers

et al. 2017

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BackgroundDeposition of aggregated amyloid beta (Aβ) protein is hallmark of Alzheimer’s disease, leading to dysfunction and apoptosis of neurons. The isoflavone phytoestrogen compound genistein (Gen) exerts a significant protective effect against Aβ25–35 induced neurotoxicity and mitochondrial damage in rat pheochromocytoma (PC12) cells. However, the mechanisms underlying Gen’s rescue remain elusive. Therefore we endeavored to research further the molecular mechanisms underlying Gen’s inhibition of Aβ25–35 induced apoptosis of neurons.ResultsWe found that Gen dramatically suppressed the activation by Aβ25–35 of p-c-Jun N-terminal kinase (p-JNK), and also inhibited the JNK-dependent decreased of Bcl-w and increased of Bim. Furthermore, Gen significantly reduced the cytoplasmic concentrations of cytochrome c and Smac protein as well as caspase-3 activity. Additionally, pretreatment with JNK inhibitor SP600125 effectively suppressed Aβ25–35 induced PC12 cell cytotoxicity.ConclusionTaken together, the results suggested that Gen protects PC12 cells from Aβ25–35 induced neurotoxicity by interfering with p-JNK activation, thus attenuating the JNK-dependent apoptosis through the mitochondrial pathway. These findings constitute novel insights into the pathway for Aβ25–35 toxicity, and the neuroprotective action of Gen.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-016-0329-9) contains supplementary material, which is available to authorized users.

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“…In 2012, a paper by Gary Landreth and his colleagues described that an old drug used for cancer treatment, bexarotene, could be useful in the treatment of Alzheimer's disease. 17 These are promising old drugs that could be used in this devastating disease, but importantly they have to be tested in humans. The results in mouse models of Alzheimer's were spectacular, Aβ load in brain was lowered, and cognition was clearly improved in the treated animals.…”

Section: New Effects Of Old Drugsmentioning

confidence: 99%

“…16 When we tested genistein in the APP/PS1 model of Alzheimer's disease, a very clear lowering of the amyloid load was observed and an increase in cognition similar to that observed with bexarotene was found. 17 These are promising old drugs that could be used in this devastating disease, but importantly they have to be tested in humans. As stated below, animal models are only models and even if the results of old drugs that are now applied for Alzheimer's disease therapeutics are very encouraging, only tests carried out in humans suffering from the disease will provide a definitive answer as to whether these old drugs can be used for Alzheimer's therapeutics.…”

Section: New Effects Of Old Drugsmentioning

confidence: 99%

Alzheimer's disease: Only prevention makes sense

Viña

Sanz-Ros

2018

Eur J Clin Investigation

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Alzheimer's disease therapeutics is one of the most important endeavours in today's clinical investigation. Over more than 30 years of research, no disease-modifying treatment has been approved by either the FDA or the EMA to treat Alzheimer's disease. Recently, the evidence of pathological alterations in the brain tissue has been gathered showing that the signs of brain damage appear more than 20 years before the onset of Alzheimer's dementia. The major aim of this review is to underpin the idea that in Alzheimer's therapeutics, only prevention makes sense. It is difficult to visualise that would-be patients may be treated with endovenous administration of antibodies for several years to delay the onset of dementia. Rather, changes in lifestyle that should be specific, stratified and personalised are a likely alternative to delay the transition from asymptomatic Alzheimer's to minimal cognitive impairment and from there to dementia. These efforts are of the utmost importance. If we could delay the onset of full-blown dementia by 5 years, the number of demented patients would be almost halved. Thus, emphasis on preventive measures that can be implemented for decades must be supported. This approach, where even mild changes in cognition are of the greatest importance, cannot be underestimated in terms of both the individual and society's viewpoints.

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Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer’s Disease

Cited by 79 publications

References 44 publications

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

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

Genistein protects against Aβ25–35 induced apoptosis of PC12 cells through JNK signaling and modulation of Bcl-2 family messengers

Alzheimer's disease: Only prevention makes sense

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