Metabolic study of Alzheimer’s disease using mutant C. elegans

Abstract

Alzheimer's disease (AD) is associated with chronic neurodegeneration and is the cause of the most common form of dementia. The main hallmarks of AD are aggregates of amyloid beta (Aβ) and formation of hyperphosphorylated tau neurofibrillary tangles (NFTs). Unfortunately, after more than 100 years of research the exact cause(s) and mechanisms involved in AD progression remain unclarified. Evidence indicates that impaired mitochondrial bioenergetics may precede by decades, the neurodegeneration and cognitive decline associated with AD. Moreover, a genetic association of the core metabolic enzyme dihydrolipoamide dehydrogenase (DLD) with late-onset AD and reduced activity of DLD-containing enzymes suggests glucose hypo-metabolism as a possible cause of AD. Contrary to this, improvements of AD symptoms under caloric restriction or other means of reducing-glucose dependent energy metabolism supports an alternative hypothesis that a decrease in glucose metabolism may be protective. In the present study, we used mutant Caenorhabditis elegans (C. elegans) to investigate the effect of glucose metabolism on AD progression. We initially looked at the role of suppressed DLD-1, and then we focused on the effect of high glucose in AD pathogenesis.Transgenic expression of Aβ in C. elegans causes both phenotypic and behavioral defects and results in accumulation of toxic Aβ oligomers, culminating in protein aggregation as is normally associated with AD pathophysiology. Aβ expression in worm muscle causes agedependent progressive paralysis and impaired acetylcholine neurotransmission while neuronal Aβ expression results in defective chemotaxis and impaired serotonin sensitivity as well as reduced fecundity and egg hatching. Suppression of the dld-1 gene alleviated paralysis, improved acetylcholine neurotransmission, enhanced chemotaxis and restored normal sensitivity to serotonin.dld-1 gene suppression also protects vitality as indicated by improved fecundity and egg hatching.Interestingly, protective effects of dld-1 suppression could be reversed using the calcium ionophore (CaI), indicating that the protective mechanism involves calcium signaling. Each of these beneficial effects of dld-1 gene suppression could be mimicked using a specific, small molecule inhibitor of the DLD-1 enzyme, 5-methoxyindole-2-carboxylic acid (MICA).High glucose levels are associated with the metabolic disorder, diabetes, which is a major risk factor for AD. In fact, it has been suggested that AD is a neural form of diabetes, type 3 diabetes. If true, drugs used to treat diabetes could act as possible treatments for AD. In this study, I investigated the effect of elevated glucose, the glucose metabolism inhibitor, 2-deoxy-d-glucose ii (2DOG) as well as the anti-diabetes drugs, metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on AD progression. Elevated glucose in the growth medium induced hyperactivity, which interfered with the paralysis assays, but it was seen to impair cholinergic neurotransmission, egg laying and hatc...