Cellular and Molecular Mechanisms Underlying Perturbed Energy Metabolism and Neuronal Degeneration in Alzheimer's and Parkinson's Diseases

Abstract

Synaptic degeneration and death of nerve cells are defining features of Alzheimer's disease (AD) and Parkinson's disease (PD), the two most prevalent age-related neurodegenerative disorders. In AD, neurons in the hippocampus and basal forebrain (brain regions that subserve learning and memory functions) are selectively vulnerable. In PD dopamine-producing neurons in the substantia nigra-striatum (brain regions that control body movements) selectively degenerate. Studies of postmortem brain tissue from AD and PD patients have provided evidence for increased levels of oxidative stress, mitochondrial dysfunction and impaired glucose uptake in vulnerable neuronal populations. Studies of animal and cell culture models of AD and PD suggest that increased levels of oxidative stress (membrane lipid peroxidation, in particular) may disrupt neuronal energy metabolism and ion homeostasis, by impairing the function of membrane ion-motive ATPases and glucose and glutamate transporters. Such oxidative and metabolic compromise may there-by render neurons vulnerable to excitotoxicity and apoptosis. Studies of the pathogenic mechanisms of AD-linked mutations in amyloid precursor protein (APP) and presenilins strongly support central roles for perturbed cellular calcium homeostasis and aberrant proteolytic processing of APP as pivotal events that lead to metabolic compromise in neurons. Specific molecular "players" in the neurodegenerative processes in AD and PD are being identified and include Par-4 and caspases (bad guys) and neurotrophic factors and stress proteins (good guys). Interestingly, while studies continue to elucidate cellular and molecular events occurring in the brain in AD and PD, recent data suggest that both AD and PD can manifest systemic alterations in energy metabolism (e.g., increased insulin resistance and dysregulation of glucose metabolism). Emerging evidence that dietary restriction can forestall the development of AD and PD is consistent with a major "metabolic" component to these disorders, and provides optimism that these devastating brain disorders of aging may be largely preventable.

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

“…Multiple lines of evidence point to the role of mitochondrial damage and oxidative stress as the major contributing factors to the pathogenesis of age-related neurodegenerative diseases, such as Parkinson's disease (PD) (Beal, 2003;Exner et al, 2012;Gille et al, 2004;Hauser and Hastings, 2012;Jenner, 2003;Mattson et al, 1999;Schapira, 2007). For example, a significant decrease in complex I activity of the mitochondrial respiratory chain, accompanied by reduced levels of coenzyme Q 10 (CoQ 10 ), is found in the brain and platelets of PD patients (Hargreaves et al, 2008;Shults et al, 1998Shults et al, , 1999.…”

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

“…Although most research has focused on the effect of Tau protein tangles and A␤ plaques on neuronal function and survival, it is now well established that astrocytes also play a role in AD pathology (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In the CNS, astrocytes are indispensable for the support of neurons.…”

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

“…It is likely that these biochemical alterations in advance signal the behavioral and histological pathogenesis of Tg-hCTF99/B6 mice. Neuronal loss is a central hallmark of the AD brain and eventually leads to severe or irreversible cognitive and psychiatric dysfunctions (Mattson et al, 1999). Questions such as how this prior occurrence of biochemical and histological changes specifically affects the process of neuronal loss, which factors in the aging brain critically lead to neuronal loss and behavioral impairments, what the neuronal properties of the degenerating neurons are, and what strategy is needed to delay or protect the pathophysiology of the AD-like brain can potentially be answered using this Tg-hCTF99/B6 model.…”