Whole Exome Sequencing Reveals a Novel APOE Mutation in a Patient With Sporadic Early-Onset Alzheimer's Disease

Laffoon

et al. 2023

ADR

After age, polymorphisms of the Apolipoprotein E (APOE) gene are the biggest risk factor for the development of Alzheimer’s disease (AD). During our investigation to discovery biomarkers in plasma, using 2D gel electrophoresis, we found an individual with and unusual apoE isoelectric point compared to APOE ɛ2, ɛ3, and ɛ4 carriers. Whole exome sequencing of APOE from the donor confirmed a single nucleotide polymorphism (SNP) in exon 4, translating to a rare Q222K missense mutation. The apoE ɛ4 (Q222K) mutation did not form dimers or complexes observed for apoE ɛ2 & ɛ3 proteins.

Section: Introductionmentioning

confidence: 99%

Discovery of a Missense Mutation (Q222K) of the APOE Gene from the Australian Imaging, Biomarker and Lifestyle Study

Laffoon

et al. 2023

ADR

The Contributions of the Endolysosomal Compartment and Autophagy to APOE ɛ4 Allele-Mediated Increase in Alzheimer’s Disease Risk

Asiamah,

Feng,

Guo

et al. 2024

JAD

Apolipoprotein E4 (APOE4), although yet-to-be fully understood, increases the risk and lowers the age of onset of Alzheimer’s disease (AD), which is the major cause of dementia among elderly individuals. The endosome-lysosome and autophagy pathways, which are necessary for homeostasis in both neurons and glia, are dysregulated even in early AD. Nonetheless, the contributory roles of these pathways to developing AD-related pathologies in APOE4 individuals and models are unclear. Therefore, this review summarizes the dysregulations in the endosome-lysosome and autophagy pathways in APOE4 individuals and non-human models, and how these anomalies contribute to developing AD-relevant pathologies. The available literature suggests that APOE4 causes endosomal enlargement, increases endosomal acidification, impairs endosomal recycling, and downregulates exosome production. APOE4 impairs autophagy initiation and inhibits basal autophagy and autophagy flux. APOE4 promotes lysosome formation and trafficking and causes ApoE to accumulate in lysosomes. APOE4-mediated changes in the endosome, autophagosome and lysosome could promote AD-related features including Aβ accumulation, tau hyperphosphorylation, glial dysfunction, lipid dyshomeostasis, and synaptic defects. ApoE4 protein could mediate APOE4-mediated endosome-lysosome-autophagy changes. ApoE4 impairs vesicle recycling and endosome trafficking, impairs the synthesis of autophagy genes, resists being dissociated from its receptors and degradation, and forms a stable folding intermediate that could disrupt lysosome structure. Drugs such as molecular correctors that target ApoE4 molecular structure and enhance autophagy may ameliorate the endosome-lysosome-autophagy-mediated increase in AD risk in APOE4 individuals.

Neural Regeneration Research

Genetic and epigenetic targets of natural dietary compounds as anti-Alzheimer’s agents

Castillo-Ordoñez,

Cajas-Salazar,

Velasco-Reyes

2023

Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults. Pathogenic factors, such as oxidative stress, an increase in acetylcholinesterase activity, mitochondrial dysfunction, genotoxicity, and neuroinflammation are present in this syndrome, which leads to neurodegeneration. Neurodegenerative pathologies such as Alzheimer’s disease are considered late-onset diseases caused by the complex combination of genetic, epigenetic, and environmental factors. There are two main types of Alzheimer’s disease, known as familial Alzheimer’s disease (onset < 65 years) and late-onset or sporadic Alzheimer’s disease (onset ≥ 65 years). Patients with familial Alzheimer’s disease inherit the disease due to rare mutations on the amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) genes in an autosomal-dominantly fashion with closely 100% penetrance. In contrast, a different picture seems to emerge for sporadic Alzheimer’s disease, which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology. Importantly, the fundamental pathophysiological mechanisms driving Alzheimer’s disease are interfaced with epigenetic dysregulation. However, the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer’s disease or following injury or stroke in humans. In recent years, there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer’s disease. Through epigenetic mechanisms, such as DNA methylation, non-coding RNAs, histone modification, and chromatin conformation regulation, natural compounds appear to exert neuroprotective effects. While we do not purport to cover every in this work, we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer’s disease-related genes.