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Signaling Mechanisms of Selective PPAR? Modulators in Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPAR?) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPAR? more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPAR? agonists influence various pathologies in AD with emphasis on development of novel selective PPAR? modulators.

SUBMITTER: Govindarajulu M

PROVIDER: S-EPMC6215547 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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

Govindarajulu Manoj M Pinky Priyanka D PD Bloemer Jenna J Ghanei Nila N Suppiramaniam Vishnu V Amin Rajesh R

PPAR research 20181021

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPAR<i>γ</i>) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit ...[more]

PMID: 30420872

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Project description:?-Secretase is an aspartyl intramembranal protease composed of presenilin, Nicastrin, Aph1, and Pen2 with 19 transmembrane domains. ?-Secretase cleaves the amyloid precursor proteins (APP) to release A? peptides that likely play a causative role in the pathogenesis of Alzheimer's disease (AD). In addition, ?-secretase cleaves Notch and other type I membrane proteins. ?-Secretase inhibitors (GSIs) have been developed and used for clinical studies. However, clinical trials have shown adverse effects of GSIs that are potentially linked with nondiscriminatory inhibition of Notch signaling, overall APP processing, and other substrate cleavages. Therefore, these findings call for the development of disease-modifying agents that target ?-secretase activity to lower levels of A?42 production without blocking the overall processing of ?-secretase substrates. ?-Secretase modulators (GSMs) originally derived from nonsteroidal anti-inflammatory drugs (NSAIDs) display such characteristics and are the focus of this review. However, first-generation GSMs have limited potential because of the low potency and undesired neuropharmacokinetic properties. This generation of GSMs has been suggested to interact with the APP substrate, ?-secretase, or both. To improve the potency and brain availability, second-generation GSMs, including NSAID-derived carboxylic acid and non-NSAID-derived heterocyclic chemotypes, as well as natural product-derived GSMs have been developed. Animal studies of this generation of GSMs have shown encouraging preclinical profiles. Moreover, using potent GSM photoaffinity probes, multiple studies unambiguously have showed that both carboxylic acid and heterocyclic GSMs specifically target presenilin, the catalytic subunit of ?-secretase. In addition, two types of GSMs have distinct binding sites within the ?-secretase complex and exhibit different A? profiles. GSMs induce a conformational change of ?-secretase to achieve modulation. Various models are proposed and discussed. Despite the progress of GSM research, many outstanding issues remain to be investigated to achieve the ultimate goal of developing GSMs as effective AD therapies.

Dataset Information

Signaling Mechanisms of Selective PPAR? Modulators in Alzheimer's Disease.

Publications

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

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Dataset Information

Signaling Mechanisms of Selective PPAR? Modulators in Alzheimer's Disease.

Publications

Signaling Mechanisms of Selective PPAR&lt;i&gt;γ&lt;/i&gt; Modulators in Alzheimer's Disease.

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OmicsDI is part of the ELIXIR infrastructure

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