bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023‒02‒19
four papers selected by
Mikaila Chetty
Goa University

  1. Front Aging Neurosci. 2022 ;14 1090109
      Accumulation of misfolded protein aggregates is a hallmark event in many age-related protein misfolding disorders, including some of the most prevalent and insidious neurodegenerative diseases. Misfolded protein aggregates produce progressive cell damage, organ dysfunction, and clinical changes, which are common also in natural aging. Thus, we hypothesized that aging is associated to the widespread and progressive misfolding and aggregation of many proteins in various tissues. In this study, we analyzed whether proteins misfold, aggregate, and accumulate during normal aging in three different biological systems, namely senescent cells, Caenorhabditis elegans, and mouse tissues collected at different times from youth to old age. Our results show a significant accumulation of misfolded protein aggregates in aged samples as compared to young materials. Indeed, aged samples have between 1.3 and 2.5-fold (depending on the biological system) higher amount of insoluble proteins than young samples. These insoluble proteins exhibit the typical characteristics of disease-associated aggregates, including insolubility in detergents, protease resistance, and staining with amyloid-binding dye as well as accumulation in aggresomes. We identified the main proteins accumulating in the aging brain using proteomic studies. These results show that the aged brain contain large amounts of misfolded and likely non-functional species of many proteins, whose soluble versions participate in cellular pathways that play fundamental roles in preserving basic functions, such as protein quality control, synapsis, and metabolism. Our findings reveal a putative role for protein misfolding and aggregation in aging.
    Keywords:  aggresomes; aging; amyloid; prions; protein misfolding; proteostasis; senescence
  2. Br J Pharmacol. 2023 Feb 15.
      Mitochondria and mitochondria-mediated signaling pathways are known to control synaptic signaling as well as long-lasting changes in neuronal structure and function. Mitochondrial impairment is linked to synaptic dysfunction in normal aging and age-associated neurodegenerative ailments including Parkinson's disease (PD) and Alzheimer's disease (AD). Both proteolysis and mitophagy perform a major role in neuroprotection by maintaining a healthy mitochondrial population during aging. Mitophagy, a highly evolutionarily conserved cellular process, helps in the clearance of damaged mitochondria and thereby maintains the mitochondrial and metabolic balance, energy supply, neuronal survival, and neuronal health. Besides the maintenance of brain homeostasis, hippocampal mitophagy also helps in synapse formation, axonal development, dopamine release, and long-term depression. In contrast, defective mitophagy contributes to aging and age-related neurodegeneration by promoting the accumulation of damaged mitochondria leading to cellular dysfunction. Exercise, stress management, maintaining healthy mitochondrial dynamics, and administering natural or synthetic pharmacological compounds are some of the strategies used for neuroprotection during aging and age-related neurological diseases. The current review discusses the impact of defective mitophagy in aging and age-associated neurodegenerative conditions, the underlying molecular pathways, and potential therapies based on recently elucidated mitophagy-inducing strategies.
    Keywords:  Aging; Mitochondrial dysfunction; Mitophagy; Neurodegeneration; Pharmacological compounds; Therapeutic interventions
  3. RSC Chem Biol. 2023 Feb 08. 4(2): 121-131
      The discovery of effective therapeutics targeting amyloid-β (Aβ) aggregates for Alzheimer's disease (AD) has been very challenging, which suggests its complicated etiology associated with multiple pathogenic elements. In AD-affected brains, highly concentrated metals, such as copper and zinc, are found in senile plaques mainly composed of Aβ aggregates. These metal ions are coordinated to Aβ and affect its aggregation and toxicity profiles. In this review, we illustrate the current view on molecular insights into the assembly of Aβ peptides in the absence and presence of metal ions as well as the effect of metal ions on their toxicity.
  4. Res Sq. 2023 Feb 01. pii: [Epub ahead of print]
      An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes are key to unleashing Aβ effects in pathological tau phosphorylation. In a large study ( n =1,016) across three cohorts, we tested whether astrocyte reactivity modulates the association of Aβ with plasma tau phosphorylation in CU people. We found that Aβ pathology was associated with increased plasma phosphorylated tau levels only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau-PET analysis revealed that tau tangles accumulated as a function of Aβ burden only in CU Ast+ individuals with a topographic distribution compatible with early AD. Our findings suggest that increased astrocyte reactivity is an important upstream event linking Aβ burden with initial tau pathology which might have implications for the biological definition of preclinical AD and for selecting individuals for early preventive clinical trials.