Signaling Mechanisms of Selective PPAR<i>γ</i> Modulators in Alzheimer’s Disease

Govindarajulu, Manoj; Pinky, Priyanka D.; Bloemer, Jenna; Ghanei, Nila; Suppiramaniam, Vishnu; Amin, Rajesh

doi:10.1155/2018/2010675

Cited by 53 publications

(35 citation statements)

References 185 publications

(181 reference statements)

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“…Nowadays, the agonist of PPAR gamma (PPARγ) is promising treatment for neuroinflammation-related condition eg. Alzheimer's disease, Parkinson's disease, and stroke (Govindarajulu et al, 2018 ; Wen et al, 2018 ; Lee et al, 2019 ). It was demonstrated that PPAR attenuated the release of pro-inflammatory cytokines and oxidative stress promotors.…”

Section: Hiv-1 and Glutamate Neurotoxicity—the Role Of Glutamate Recementioning

confidence: 99%

The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

Górska

Eugenín

2020

Front. Cell. Infect. Microbiol.

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Glutamate (Glu) is the most abundant excitatory neurotransmitter in the central nervous system (CNS). HIV-1 and viral proteins compromise glutamate synaptic transmission, resulting in poor cell-to-cell signaling and bystander toxicity. In this study, we identified that myeloid HIV-1-brain reservoirs survive in Glu and glutamine (Gln) as a major source of energy. Thus, we found a link between synaptic compromise, metabolomics of viral reservoirs, and viral persistence. In the current manuscript we will discuss all these interactions and the potential to achieve eradication and cure using this unique metabolic profile.

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Section: Hiv-1 and Glutamate Neurotoxicity—the Role Of Glutamate Recementioning

confidence: 99%

The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

Górska

Eugenín

2020

Front. Cell. Infect. Microbiol.

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“…Although evidence suggests that peroxisome proliferator-activated receptor γ (PPARγ) modulators like thiazolidinediones (TZD) improve neuroinflammation and synaptic plasticity [86], the detailed mechanism for these effects is yet to be explored [87]. However, insulin is generally regarded as safer due to the adverse effects of TZDs on other organ systems.…”

Section: Role Of Apoe In Brain Insulin Signaling and Glucose Metabolismmentioning

confidence: 99%

The role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions

et al. 2019

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Alzheimer’s disease (AD) is the leading cause of dementia affecting almost 50 million people worldwide. The ε4 allele of Apolipoprotein E (APOE) is the strongest known genetic risk factor for late-onset AD cases, with homozygous APOE4 carriers being approximately 15-times more likely to develop the disease. With 25% of the population being APOE4 carriers, understanding the role of this allele in AD pathogenesis and pathophysiology is crucial. Though the exact mechanism by which ε4 allele increases the risk for AD is unknown, the processes mediated by APOE, including cholesterol transport, synapse formation, modulation of neurite outgrowth, synaptic plasticity, destabilization of microtubules, and β-amyloid clearance, suggest potential therapeutic targets. This review will summarize the impact of APOE on neurons and neuronal signaling, the interactions between APOE and AD pathology, and the association with memory decline. We will then describe current treatments targeting APOE4, complications associated with the current therapies, and suggestions for future areas of research and treatment.

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“…The latter, complement reports that animal models of diabetes exhibit cognitive impairments and features of AD neuropathology (Clodfelder-Miller et al, 2006). Together, these data make it plausible that AD may be amenable to antidiabetic treatments (for review, see Govindarajulu et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Activated PPARγ Abrogates Misprocessing of Amyloid Precursor Protein, Tau Missorting and Synaptotoxicity

Moosecker

Gomes

Dioli

et al. 2019

Front. Cell. Neurosci.

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Type 2 diabetes increases the risk for dementia, including Alzheimer’s disease (AD). Pioglitazone (Pio), a pharmacological agonist of the peroxisome proliferator-activated receptor γ (PPARγ), improves insulin sensitivity and has been suggested to have potential in the management of AD symptoms, albeit through mostly unknown mechanisms. We here investigated the potential of Pio to counter synaptic malfunction and loss, a characteristic of AD pathology and its accompanying cognitive deficits. Results from experiments on primary mouse neuronal cultures and a human neural cell line (SH-SY5Y) show that Pio treatment attenuates amyloid β (Aβ)-triggered the pathological (mis-) processing of amyloid precursor protein (APP) and inhibits Aβ-induced accumulation and hyperphosphorylation of Tau. These events are accompanied by increased glutamatergic receptor 2B subunit (GluN2B) levels that are causally linked with neuronal death. Further, Pio treatment blocks Aβ-triggered missorting of hyperphosphorylated Tau to synapses and the subsequent loss of PSD95-positive synapses. These latter effects of Pio are PPARγ-mediated since they are blocked in the presence of GW9662, a selective PPARγ inhibitor. Collectively, these data show that activated PPARγ buffer neurons against APP misprocessing, Tau hyperphosphorylation and its missorting to synapses and subsequently, synaptic loss. These first insights into the mechanisms through which PPARγ influences synaptic loss make a case for further exploration of the potential usefulness of PPARγ agonists in the prevention and treatment of synaptic pathology in AD.

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Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease

Cited by 53 publications

References 185 publications

The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

The role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions

Activated PPARγ Abrogates Misprocessing of Amyloid Precursor Protein, Tau Missorting and Synaptotoxicity

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