Therapeutic potential of nuclear receptor agonists in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by an extensive accumulation of amyloid-β (Aβ) peptide, which triggers a set of deleterious processes, including synaptic dysfunction, inflammation, and neuronal injury, leading to neuronal loss and cognitive impairment. A large body of evidence supports that nuclear receptor (NR) activation could be a promising therapeutic approach for AD. NRs are ligand-activated transcription factors that regulate gene expression and have cell type-specific effects. In this review, we discuss the mechanisms that underlie the beneficial effects of NRs in AD. Moreover, we summarize studies reported in the last 10-15 years and their major outcomes arising from the pharmacological targeting of NRs in AD animal models. The dissection of the pathways regulated by NRs in the context of AD is of importance in identifying novel and effective therapeutic strategies.

The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer’s Disease and Other Neurodegenerative Disorders

“…PPARs and RXR receptors activation upregulates the expression of several synaptic related genes coding proteins engaged in excitatory neurotransmission [12,36]. Probably through these mechanism agonists of PPAR-α may have a promising effect in a mouse model of aging-dependent cognitive impairments [37,38]. Moreover, it was previously reported that RXR activation increases dendritic complexity and branching of neurons and differentiation [39,40] but it seems now that PPAR-α plays a key role in these processes.…”

“…Some other last data indicate promising, positive effect of PPARs agonists [127][128][129][130][131][132][133][134][135]. Overall it seems that personalized gene-related therapy or personalized combination Reduces Aβ production [48] Decreases Aβ plaque accumulation Improves learning memory [55] Decreases Aβ accumulation and reverses memory deficits and anxiety symptoms [132] WY-14643 Decreases tau protein and inflammation markers Increases ability in Moris water test [37] GW7647 Regulates APP amyloidogenic processing Decreases the expression of sAPPβ and ability of BACE1 Reduces Aβ release and Aβ production [50] Fenofibrate Regulates oxidative stress accumulation [133] Fenofibrate Parkinson's disease Protects against the damaging effect of MPTP in a rat model Decreases inflammation [94,134] Cerebral injury Reduces suspectibility to stroke in apolipoprotein E-deficient animals Decreases cerebral infarct volume [135] of specific pharmacological compounds should be more efficient. The further studies on pharmacologically active compounds that target PGC-1α and PPARs are necessary.…”

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

“…and aging (10,11). Importantly, they play a regulatory role in diseases of aging including Alzheimer's disease (12,13), cardiovascular disease (14), and cancer (15). Given the commonality between pathogenic pathways regulated by nuclear receptors in age-related diseases and AMD, in an attempt to identify candidate receptors that may be important in disease initiation and progression, we previously developed a nuclear receptor atlas of human RPE cells, cells vulnerable in AMD (16).…”

Association between atherosclerosis and Alzheimer's disease: A systematic review and meta‐analysis

“…Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid‐β (Aβ) deposition, excessive phosphorylation of tau protein, and neurofibrillary tangles (Hardy & Selkoe, 2002; Prince et al, 2013). It has a long preclinical phase and causes impairment of cognitive, disability, and dependency of daily life (Moutinho & Landreth, 2017). AD is the most common type of dementia (Alzheimer's Association, 2016; Goodman et al, 2017) and accounts for about 60%–70% in dementia cases (World Health Organization, 2019).…”