Abstract
Age-dependent neurodegenerative disorders are a set of diseases that affect millions of individuals worldwide. Apart from a small subset that are the result of well-defined inherited autosomal dominant gene mutations (e.g., those encoding the β-amyloid precursor protein and presenilins), our understanding of the genetic network that underscores their pathology, remains scarce. Genome-wide association studies (GWAS) especially in Alzheimer's disease patients and research in Parkinson's disease have implicated inflammation and the innate immune response as risk factors. However, even if GWAS etiology points toward innate immunity, untangling cause, and consequence is a challenging task. Specifically, it is not clear whether predisposition to de-regulated immunity causes an inadequate response to protein aggregation (such as amyloid or α-synuclein) or is the direct cause of this aggregation. Given the evolutionary conservation of the innate immune response in Drosophila and humans, unraveling whether hyperactive immune response in glia have a protective or pathological role in the brain could be a potential strategy in combating age-related neurological diseases.
Highlights
Aging is characterized by the time-dependent deterioration of cellular function and fitness of an organism, accompanied by an increased susceptibility to diseases [1]
The antimicrobial peptides (AMPs) are regulated by two signaling pathways: The Toll pathway, which was the first in the family of Toll-like receptors discovered in a wide range of organisms from sea urchins to humans, and the IMD pathway homologous to the tumor necrosis factor receptor 1 (TNFR1) in mammals [107]
The precise mechanism of the development of neurodegenerative diseases is still unknown and this presents a challenge for the development of treatments and therapies
Summary
The innate immune system, an immune reaction with broad specificity, is an organism’s first line of defense. Dorsal and Dif translocates to the nucleus and leads to the transcription of AMPs and other target genes [reviewed in [114]] Another evolutionarily conserved singling cascade is the immune deficiency (Imd) pathway (Figure 1), the activation of which is achieved with the help of two PGRP receptors namely, PGRP-LC and PCRP-LE. An interesting connection between autophagy, immunity and neurodegeneration was recently made by the observation that mutants for the Cdk protein kinase have increased AMP expression in the brain and loss of dopaminergic neurons. Age-dependent neurodegeneration in a model of pTBI Reduction of PolyQ-mediated neurodegeneration Increased resistance to paraquat, rescue of motility defects and DA neurons in a Drosophila model of PD Suppression of retinal degeneration in norpA mutants Better clearance of Aβ-amyloid Neuronal death We only list those showing a causative link between immune activity or immune-related signaling and neurological phenotype. Westfall et al explored how symbiotic and probiotic formulation can influence gut brain signaling and delay the progression of AD [147]
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