Central and Peripheral Metabolic Defects Contribute to the Pathogenesis of Alzheimer's Disease: Targeting Mitochondria for Diagnosis and Prevention

Abstract

Significance: Epidemiological studies indicate that metabolic disorders are associated with an increased risk for Alzheimer's disease (AD). Metabolic remodeling occurs in the central nervous system (CNS) and periphery, even in the early stages of AD. Mitochondrial dysfunction has been widely accepted as a molecular mechanism underlying metabolic disorders. Therefore, focusing on early metabolic changes, especially from the perspective of mitochondria, could be of interest for early AD diagnosis and intervention. Recent Advances: We and others have identified that the levels of several metabolites are fluctuated in the periphery before their accumulation in the CNS, which plays an important role in the pathogenesis of AD. Mitochondrial remodeling is likely one of the earliest signs of AD, linking nutritional imbalance to cognitive deficits. Notably, by improving mitochondrial function, mitochondrial nutrients efficiently rescue cellular metabolic dysfunction in the CNS and periphery in individuals with AD. Critical Issues: Peripheral metabolic disorders should be intensively explored and evaluated for the early diagnosis of AD. The circulating metabolites derived from mitochondrial remodeling represent novel potential diagnostic biomarkers for AD that are more readily detected than CNS-oriented biomarkers. Moreover, mitochondrial nutrients provide a promising approach to preventing and delaying AD progression. Future Directions: Abnormal mitochondrial metabolism in the CNS and periphery is involved in AD pathogenesis. More clinical studies provide evidence for the suitability and reliability of circulating metabolites and cytokines for the early diagnosis of AD. Targeting mitochondria to rewire cellular metabolism is a promising approach to preventing AD and ameliorating AD-related metabolic disorders.

Curcugreen Treatment Prevented Splenomegaly and Other Peripheral Organ Abnormalities in 3xTg and 5xFAD Mouse Models of Alzheimer’s Disease

“…Although the central nervous system is the most vulnerable area affected by Alzheimer's disease (AD), recent evidence indicates that AD is a multi-organ disorder, which includes metabolic dysfunction and pathological processes in the peripheral organs [30]. Therefore, we were interested in investigating changes in the peripheral organs in two animal models of AD.…”

“…Therefore, many investigators have developed different lipids or nano-conjugated formulations to increase their bioavailability. For example, solid lipid curcumin particles (SLCP) have been shown to prevent neuropathology in AD and other neurodegenerative diseases [25,26,29,30]. More recently, we have been investigating the effects of curcugreen (CGR) on animal models of AD.…”

Methylation factor MRPL15 identified as a potential biological target in Alzheimer’s disease

“…MRPL15 is a mitochondrial ribosomal protein necessary for protein synthesis. Mitochondrial dysfunction was found to be an important marker of AD [ 26 , 27 ]. MRPL15 may also be related to the closure or disorder of the biological function of mitochondria and in the function of energy metabolism in schizophrenia [ 28 ].…”

The Other Side of Alzheimer’s Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers

“…Considering the central role of mitochondria in AD pathophysiology, a major issue for AD early diagnosis is the identification of new candidate biomarkers related to mitochondrial enzymes and metabolism in peripheral districts such as CSF and blood. Even though the establishment of reliable and consistent mitochondrial biomarkers for AD is still not achieved, studies have been carried out to shed light on the possible use of mitochondrial markers for this purpose [172]. For example, a recent study has demonstrated the possibility of detecting alterations in the expression of nuclear and mitochondrial encoded Oxidative Phosphorylation (OXPHOS) genes in blood samples from AD and MCI patients [173] (Figure 5).…”