Charnoly body as a novel biomarker of nutritional stress in Alzheimer’s Disease

Background: The Charnoly body (CB) was discovered as a universal biomarker of cell injury in the developing undernourished rat cerebellar Purkinje neurons and in the intrauterine Domoic acid and Kainic acid-exposed mice hippocampus and hypothalamic neurons. The incidence of CB increased with the severity of nutritional and environmental neurotoxic insult. Purpose: We proposed that stress (nutritional and environmental) induced cortisol release augments, whereas metallothioneins (MTs), insulin-like growth factor (IGF-1), and brain-derived neurotropic factor (BDNF) inhibit CB formation to prevent progressive neurodegeneration, early morbidity, and mortality in Alzheimer’s disease (AD). Results: CB is a pre-apoptotic biomarker of compromised mitochondrial bioenergetics, formed in the most vulnerable cell in response to nutritional stress, intrauterine infection, environmental toxins, and/or drug abuse due to free radical overproduction and mitochondrial genome down- regulation. It appears as a pleomorphic, electron-dense multi-lamellar, quasi-crystalline stack of degenerated mitochondrial membranes in highly susceptible neurons and may be induced by microbial infection. CB formation was accompanied with stunted neuritogenesis in the aging mitochondrial genome knock out (RhOmgko) human dopaminergic (SK-N-SH, SHS-Y-5Y) neurons due to down-regulation of ubiquinone NADH oxidoreductase (complex-1). Transfection of RhOmgko neurons with ubiquinone NADH oxidoreductase (complex-1) gene and CoQ10, inhibited CB formation and augmented neuritogenesis, as confirmed in α-synuclein- metallothioneins triple knock out and weaver mutant mice. CB formation was attenuated in MTs- over-expressing weaver mutant mice. Findings: Accumulation of CB at the junction of axon hillock impairs axoplasmic transport of enzymes, neurotransmitters, hormones, neurotropic factors (NGF, BDNF), and mitochondria at the synaptic terminals cause cognitive impairment, early morbidity, and mortality. Nonspecific induction of CB causes alopecia, myelosuppression, and GIT symptoms in multi-drug-resistant malignancies. Antioxidants and MTs inhibit CB formation as free radical scavengers by zinc- mediated transcriptional regulation of genes involved in growth, proliferation, differentiation, and development. Consequently, drugs may be developed to prevent CB formation and/or enhance charnolophagy as a basic molecular mechanism of intracellular detoxification to avert cognitive impairments in AD. Conclusion: Brain regional monoamine oxidase-specific CBs can be detected by 11C or 18F- labeled MAO-A or MAO-B inhibitors in vivo, in addition to 18FdG-PET neuroimaging to quantitatively assess and improve the mitochondrial bioenergetics in AD. Conclusion: The basic understanding of sporadic AD has been a major challenge. Unlike the familial forms of AD, the genetic and environmental risks factors for sporadic AD are extensive. AD is the most common form of dementia but the identification of reliable, early and non-invasive biomarkers remains a major challenge. We have proposed novel CB-based molecular biomarkers for detecting AD from peripheral cells including: skin cells, buccal mucosa cells, platelets, and lymphocytes and highlighted that compromised mitochondrial bioenergetics triggers CB formation involved in AD, PD, Pick’s Disease. Alcoholism, Schizophrenia, chronic drug addiction (Cocaine, and METH), Down’s syndrome, autism, Prion’s disease, HD, ALS, MS, AIDs dementia, and several other chronic conditions of unknown etiopathogenesis. Nutritional stress, environmental toxins, and microbes can induce hippocampal atrophy, callosal atrophy, fronto-temporal cortical atrophy, ventriculomegaly, cerebral hyperthermia, dehydration, cerebral ischemia, stroke, and epilepsy due to free radical-induced CB formation, which can be ameliorated to a certain extent by supplementation of antioxidant-rich functional foods in old age to prevent progressive neurodegeneration, cognitive impairment, and dementia in AD and other neurodegenerative diseases. The basic advantage of antioxidants derived from functional foods (including Resveratrol, Lycopenes, Sirtuins, Rutins, Catschin, Flavonoids, and Polyphenols) is that these can pass easily through blood brain barrier and do not produce adverse side effects as noticed in other standard pharmaceutical agents. Presently, we have limited scope of removing any normal or pathological brain region because of its limited regenerative potential and serious impairment in the sensory modality due to somatotropic representation. Consequently, the therapeutic benefit of antioxidants is highly significant. However, the main limitation of antioxidants derived from functional foods and Mediterranean diets is that they have reduced potency. As a result, their therapeutic potential is also limited at this moment. Serious attempts are being made to develop specific antioxidant-loaded ROS scavenging nanoparticles to enhance their adequate delivery in the CNS and other organs for AD prevention and treatment