bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023‒03‒26
four papers selected by
Mikaila Chetty
Goa University

  1. Heliyon. 2023 Mar;9(3): e14387
      Mitochondrial dysfunction remains a pivotal mechanism in manifold neurodegenerative diseases. Mitochondrial homeostasis within the cell is an essential aspect of cell biology. Mitochondria, the power-generating organelle of the cell, have a dominant role in several processes associated with genomic integrity and cellular equilibrium. They are involved in maintaining optimal cell functioning and ensuring guidance against possible DNA damage, which could lead to mutations and the onset of diseases. Conversely, system perturbations, which could be due to environmental factors or senescence, induce changes in the physiological balance and result in mitochondrial function impairment. As a result, we present a general overview of the pathological pathways involved in Alzheimer's and Parkinson's diseases caused by changes in mitochondrial homeostasis. The focal point of this review is on mitochondrial dysfunction being a significant condition in the onset of neuronal disintegration. We explain the pathways associated with the dysfunction of the mitochondria, which are common among the most recurring neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Are mitochondrial dysfunctions an early event in the progression of neuropathological processes? We discovered that mtDNA mutation is a major contributor to the metabolic pathology of most neurological disorders, causing changes in genes important for physiological homeostasis. As a result, genetic changes in presenilin, Amyloid-, ABAD, DJ-1, PINK-1, PARKIN, alpha-synuclein, and other important controlling genes occur. Therefore, we suggest possible therapeutic solutions.
    Keywords:  Alzheimer's disease; Amyloid β; Mitochondrial dysfunction; Neurodegeneration; Parkin; Parkinson's disease
  2. Nat Metab. 2023 Mar 23.
      Astrocytes provide key neuronal support, and their phenotypic transformation is implicated in neurodegenerative diseases. Metabolically, astrocytes possess low mitochondrial oxidative phosphorylation (OxPhos) activity, but its pathophysiological role in neurodegeneration remains unclear. Here, we show that the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet (LD) accumulation followed by neurodegeneration that recapitulates key features of Alzheimer's disease (AD), including synaptic loss, neuroinflammation, demyelination and cognitive impairment. Mechanistically, when FA load overwhelms astrocytic OxPhos capacity, elevated acetyl-CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. Intercellularly, lipid-laden reactive astrocytes stimulate neuronal FA oxidation and oxidative stress, activate microglia through IL-3 signalling, and inhibit the biosynthesis of FAs and phospholipids required for myelin replenishment. Along with LD accumulation and impaired FA degradation manifested in an AD mouse model, we reveal a lipid-centric, AD-resembling mechanism by which astrocytic mitochondrial dysfunction progressively induces neuroinflammation and neurodegeneration.
  3. Adv Exp Med Biol. 2023 ;1411 39-70
      Since its first description over a century ago, neurodegenerative diseases (NDDs) have impaired the lives of millions of people worldwide. As one of the major threats to human health, NDDs are characterized by progressive loss of neuronal structure and function, leading to the impaired function of the CNS. While the precise mechanisms underlying the emergence of NDDs remains elusive, association of neuroinflammation with the emergence of NDDs has been suggested. The immune system is tightly controlled to maintain homeostatic milieu and failure in doing so has been shown catastrophic. Here, we review current concepts on the cellular and molecular drivers responsible in the induction of neuroinflammation and how such event further promotes neuronal damage leading to neurodegeneration. Experimental data generated from cell culture and animal studies, gross and molecular pathologies of human CNS samples, and genome-wide association study are discussed to provide deeper insights into the mechanistic details of neuroinflammation and its roles in the emergence of NDDs.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Immune system; Multiple sclerosis; Neurodegeneration; Neuroinflammation; Parkinson’s disease; Pro-inflammatory
  4. Front Cell Neurosci. 2023 ;17 1105247
      Neuronal loss is one of the striking causes of various central nervous system (CNS) disorders, including major neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). Although these diseases have different features and clinical manifestations, they share some common mechanisms of disease pathology. Progressive regional loss of neurons in patients is responsible for motor, memory, and cognitive dysfunctions, leading to disabilities and death. Neuronal cell death in neurodegenerative diseases is linked to various pathways and conditions. Protein misfolding and aggregation, mitochondrial dysfunction, generation of reactive oxygen species (ROS), and activation of the innate immune response are the most critical hallmarks of most common neurodegenerative diseases. Thus, endoplasmic reticulum (ER) stress, oxidative stress, and neuroinflammation are the major pathological factors of neuronal cell death. Even though the exact mechanisms are not fully discovered, the notable role of mentioned factors in neuronal loss is well known. On this basis, researchers have been prompted to investigate the neuroprotective effects of targeting underlying pathways to determine a promising therapeutic approach to disease treatment. This review provides an overview of the role of ER stress, oxidative stress, and neuroinflammation in neuronal cell death, mainly discussing the neuroprotective effects of targeting pathways or molecules involved in these pathological factors.
    Keywords:  ER stress; ROS; UPR – unfolded protein response; cell death; neurodegenerative diseases; neuroinflammation; oxidative stress