Interplay among norepinephrine, NOX2, and neuroinflammation: key players in Parkinson’s disease and prime targets for therapies

Abstract

Aim: No studies have examined whether interactions between the apolipoprotein E4 (ApoE4) allele and peripheral biomarkers, hypertension, and type 2 diabetes mellitus (T2DM) may impact the neurocognitive, behavioral, and social dysfunctions in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). We aimed to clinically define and biologically validate a subgroup of aMCI subjects who take up an intermediate position between controls and AD patients. Methods:In 61 healthy controls, 60 subjects with aMCI, and 60 AD patients, we measured the features of aMCI/AD using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). A composite BIORISK score was computed using the ApoE4 allele, serum folate, albumin, white blood cells, fasting blood glucose, atherogenic index of plasma, T2DM, and hypertension.Results: Clustering and nearest neighbor analyses were unable to validate the aMCI subgroup. We constructed two z unit-based composite scores, the first indicating overall burden of cognitive, social, and behavioral deterioration (OBD) and the second reflecting the interactions among ApoE4, all other biomarkers, hypertension, and T2DM (BIORISK). We found that 40.2% of the variance in the OBD score was explained by BIORISK, ApoE4, age, and education. The OBD index was used to construct three subgroups (normal, medium, and high OBD) with the medium group (n = 45) showing mild cognitive dysfunctions (MCD) in memory, language, orientation, and ADL. People with MCD show OBD and BIORISK scores that are significantly different from controls and AD. Conclusion:Petersen's aMCI criteria cannot be validated and should be replaced by the more restrictive, biologically validated MCD class.

Roles of Transcription Factors in the Development and Reprogramming of the Dopaminergic Neurons

“…Nurr1, also known as NR4A2/NOT/TINUR, is a member of the orphan nuclear receptor family 4 (NR4A), necessary for the mdDA neurons’ development, maturation, and functional maintenance [ 46 , 69 , 70 ]. It is also involved in neuroprotection and neuroinflammation regulation by inhibiting pro-inflammatory factors in microglial and astrocytes cells [ 71 , 72 , 73 ]. Notably, in mdDA neurons, the decreased levels of Nurr1 were characterized during aging, which may be related to the increased morbidity of PD [ 74 , 75 ].…”

Intestinal Permeability, Dysbiosis, Inflammation and Enteric Glia Cells: The Intestinal Etiology of Parkinson’s Disease

“…In a cohort study, Villumsen et al [50] found individuals troubled with IBD are more susceptible to PD. Inflammation is a well-known feature of PD [51]. It has been proposed that this inflammation may be triggered by a disruption in the intestinal barrier, which exposes the system to inflammatory microbial compounds such LPS, a component of bacterial cell walls [52].…”

Role of Glia-Derived Extracellular Vesicles in Neurodegenerative Diseases

“…Under inflammatory or neurotoxic conditions, glia generally turns into a harmful phenotype accompanied by the release of EVs, contributing to the increase of DAergic neuron vulnerability and the exacerbation of neuronal death ( Wang et al, 2021 ). Results from the α-synuclein overexpression mouse model indicate that the abnormity accumulated α-synuclein can alter the pro-inflammatory gene expression profile in the glial.…”