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Role of Vitamin D and Antioxidant Functional Foods in the Prevention and Treatment of Alzheimer’s Disease Pathology
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
New tools for the study of the molecular pathways affected by this disease include genome-wide association studies and genetic sequencing. Some of the gene families being identified as relevant in disease pathogenesis by these methods include APOE, BIN1, CLU, and CD33. Involved biological pathways include immune response (ABCA7, CD33, CLU, CR1. HLA locus, MEF2C, PTK2B, TREM2), lipid metabolism (ABCA), and endocytosis (BIN1, CD2AP, EPHA1, PICAALM, SORL1) pathways (Verheijen & Sleegers, 2018).
Alzheimer's Disease
Published in Marc E. Agronin, Alzheimer's Disease and Other Dementias, 2014
Other genetic susceptibility factors for LOAD have been found on chromosomes 10, 11, and 12. These are listed in Table 4.3 and include the recently identified SORL1 gene on chromosome 11, which may govern the distribution of APP inside neurons and has been associated with a tripling of the risk of LOAD in several select populations (Rogaeva et al., 2007). Despite extensive research, none of these factors has accumulated the amount of empirical support found with the APOE ε4 gene (Reitz et al., 2011).
Pre-Clinical Approaches and Methods on Alzheimer’s Disease
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
S. R. Chandra, Pooja Mailankody
The allele of the APOE gene on chromosome 19 is associated with late-onset AD, and genes for sortilin-related receptor 1 (SORL1) and ubiquilin 1 on chromosome 1 are associated with recycling of amyloid precursor peptide (APP). There is overlap of major proteins, like amyloid and tau, in AD, with amyloid and α-synuclein in diffuse Lewy body disease (DLBD) causing problems in specificity. The amyloid hypothesis states that Aβ production and degradation is the pathology common to all types of AD and the causative genes for APP are on chromosome 9. The presenelin-1 gene on chromosome 14 causes severe, very early disease with features of parkinsonism, and is associated with about 60% of inherited AD cases. The presenelin-2 gene on chromosome 1 is a less common cause and is also involved in other diseases. APP is a part of neuronal synapses, and the corresponding gene is located on chromosome 21. Proteolysis of APP by α- or β-secretase leads to secretion of soluble fragments of amyloid alpha or beta peptide. These are subsequently cleaved by γ-secretase to generate either a gamma fragment. In early-onset AD, there is an imbalance between the Aβ42, which increases, and the Aβ40, which decreases, resulting in a propensity for aggregation (Klunk et al. 2004; Kumar et al. 2017). In screening for familial AD cases, it is better to look for presenilin-1 and APP, as they are the most common indicators. APOEε4, located on chromosome 19, is responsible for both familial and sporadic late-onset AD. Other genes which might play a role are ABCA7, CLU, which regulates the clearance of Aβ from the brain, CR1, PLD3, and TREM2, which contribute to chronic inflammation in the brain, and SORL1 and PICALM, which are involved in synaptic connectivity.
Usefulness of candidate mRNAs and miRNAs as biomarkers for mild cognitive impairment and Alzheimer’s disease
Published in International Journal of Neuroscience, 2023
Hongyun Qin, Chengping Hu, Xudong Zhao, Ming Tian, Binggen Zhu
It is reported that loss of the protein that functions as a stalled-ribosome rescue factor is linked to neuronal degeneration [31]. The dysfunction of the ribosome and its associated pathway has already been proven to occur early in AD [32]. RNA oxidation and decreased expression associated with the ribosome play important roles in AD and MCI pathogenesis [33, 34]. In addition, some mRNAs and miRNAs are proved to participate in ribosome pathway dysfunction during disease development [35, 36]. RPL11, a family member of ribosomal proteins, is crucial for the translation termination and translational accuracy in the ribosome [37]. It was reported that the synthesis of certain neuronal proteins such as LR11/SorLA is reduced in MCI [38]. A previous study showed that RPL11 is related to brain maturation [39]. RPL11 contributes to the function of ribosomal stress-challenged cortical neurons in neurodegenerative diseases [40]. Jaber et al. [41] indicated that alterations in miRNA–mRNA coupled signaling influenced the disease process of AD. In the current study, ribosome was the common pathway enriched by candidate DEGs including RPL11 and target genes of candidate DEmiRs including miR-6764-5p. Furthermore, miR-6764-5p-RPL11 was one of the miRNA–mRNA interaction in the miRNA–mRNA interaction network. Thus, we speculated that miR-6764-5p might take part in the progression of MCI and AD by targeting RPL11 and the ribosome pathway.
Genetic analysis of Vietnamese patients with early-onset Alzheimer's disease
Published in International Journal of Neuroscience, 2022
Trang Mai Tong, Thuy Thi Hong Dao, Loc Phuoc Doan, Dat Thanh Nguyen, Quynh-Tho Thi Nguyen, Thanh-Thuy Thi Do, Kiet Dinh Truong, Minh-Duy Phan, Hoai-Nghia Nguyen, Thang Cong Tran, Hoa Giang
Our study also reported eight mutations in five AD-associated genes (BIN1, CR1, CLU, PICALM, SORL1) from eight different EOAD patients. Functional prediction tools suggested that these mutations might have damaging impact to the proteins. Most recent studies have placed SORL1 as a major genetic determinant in both EOAD and LOAD [22–24]. In vitro cell culture analyses found that loss-of-function mutations in SORL1 gene induced Aβ42 and Aβ40 secretion and disrupted APP trafficking [22]. Interestingly, none of our reported mutations in these genes was similar to that in Korean EOAD cohort [10]. Even though absence of functional and biological assessment is a limitation in this study, our findings suggested the necessity of genetic screening to expand the understanding of genetic variations in different ethnic populations.
Renal amyloidosis: Pathogenesis
Published in Ultrastructural Pathology, 2021
The receptor in the surface of mesangial cells has a key component: SOR1.2 SORL1 participates in the internalization of amyloidogenic light chains into mesangial cells, and later into lysosomes for processing and fibril formation. One very important event that occurs right after the light chains interact with the mesangial cells is that the latter transform from their normal smooth muscle to a macrophage phenotype, endowing them with the machinery to actively participate in endocytosis and processing of the endocytosed amyloid precursor proteins.42,43 Internalization and trafficking of amyloidogenic light chains in mesangial cells using Rab proteins with eventual delivery to the mature lysosomal system where processing led to the formation of amyloid fibrils was demonstrated. The process of internalization was found to be clathrin-mediated. Lysosomal processing of these light chains with partial proteolysis was shown to be a crucial step in the genesis of amyloid fibrils.42–46 For example, increasing the pH of the lysosomes decreased amyloid formation. Other maneuvers, including some which changed the mesangial milieu, also altered amyloid formation.44