China
Africa
Explore chapters and articles related to this topic
Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
The remaining 5% of cases are young onset, presenting clinically prior to 65 years of age. Approximately ∼1% of young-onset cases are linked to autosomal dominant inheritance of mutations in one of the three known causative genes: Amyloid precursor protein (APP) gene: located on the long arm of chromosome 21, encodes APP, responsible for < 1% of all early-onset cases.Presenilin 1 (PSEN-1) gene: located on chromosome 14q, encodes PS-1, responsible for 50% of early-onset cases.Presenilin 2 (PSEN-2) gene: located on chromosome 1, encodes PS-2, responsible for 15–20% of early-onset cases.
Cognitive Improvement, Neuroprotective, and Nootropic Effect of Medhya Rasa¯yana Drugs in Alzheimer’s Disease
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
Rinki Kumari, Jasmit Singh, Bhargawi Mishra, Anamika Tiwari, Abaidya Nath Singh
There are two types of PSEN gene involved in the pathogenesis of AD, PSEN1 and PSEN2. The PSEN1 gene is located on chromosome 14q and regulates intracellular Ca2+ signaling and trafficking of membrane proteins, and is involved in the regulation of the stabilization of β-catenin. Studies reported that any type of mutation in the PSEN1 gene results in the formation of Aβ peptides of varying lengths, due to cleavage at different sites by γ-secretase. These peptides are highly fibrillogenic, causing increased aggregation of Aβ plaques in the brain (Brunkan and Goate, 2005). The second presenilin gene, PSEN2, is located on chromosome 1q and encodes the PS2 transmembrane protein, isoform 2 of which is found in the brain. PSEN2 mutations cause accumulation of the Aβ42 protein, which is the hallmark of AD (Cai et al., 2015).
The nervous system and the eye
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
James A.R. Nicoll, William Stewart, Fiona Roberts
The pathogenesis of Alzheimer's disease is still unclear, although there has been intense focus on the deposition of amyloid β-protein in the cortex as a putative initiating event. A small number of familial cases have a point mutation in the amyloid precursor protein (APP) gene (located on chromosome 21), from which amyloid β-protein is derived. Additional autosomal dominant, disease-causing point mutations include presenilin 1 and 2. Individuals with Down's syndrome, who have trisomy 21 and therefore three copies of the APP gene, all develop Alzheimer's disease by the age of 40 years. Deposition of amyloid β-protein has been identified as one of the earliest features of Alzheimer's disease pathology to appear in those with Down's syndrome dying at a younger age. However, a causal role for abnormal aggregation of amyloid β-protein in the pathogenesis of the common form of sporadic Alzheimer's disease has not yet been established with certainty. There is also evidence for mechanisms involving intraneuronal aggregation of the cytoskeleton-associated tau-forming tangles. Recent genome-wide association studies point to important roles for inflammation and lipid metabolism in the pathogenesis of Alzheimer's disease.
High throughput and targeted screens for prepilin peptidase inhibitors do not identify common inhibitors of eukaryotic gamma-secretase
Published in Expert Opinion on Drug Discovery, 2023
Pradip Kumar Singh, Michael S. Donnenberg
According to the MEROPS database [35], PPP are members of the A24A family of aspartyl peptidases, characterized as polytopic transmembrane endopeptidases with aspartate residues in the active site. The active site aspartate residues are located at the cytosolic face of the membrane within conserved motifs: Xa-Xa-D-Xa-Xb-X-X-X-Xa-P and Xa-G-X-G-D-Xa-K-Xa-Xa-Xa (where Xa is hydrophobic, Xb is charged, D is aspartate, and X is any amino acid) [12,36]. Mutation of either aspartate led to enzyme inactivation [12]. Interestingly, polytopic membrane aspartyl proteases with a G-X-G-D motif are also found in the eukaryotic domain of life, including in humans. For example, presenilin-1 and presenilin-2 are part of the gamma (γ)-secretase protease complex, which cleaves the amyloid precursor protein into β-amyloid [37]. Along with signal peptide peptidase, they belong to the A22 family which shares the same clan AD with PPP A24 family in the MEROPS database. A missense mutation in presenilin-1 is associated with familial Alzheimer’s disease [38]. Presenilins have two conserved membrane-embedded aspartates at the active site and, as in PPP, both are required for endoproteolysis [39]. Although the G-X-G-D motif is found in both bacterial PPP and presenilins, in PPP the motif resides in the cytosol, whereas in eukaryotic enzymes it is embedded in the membrane [12,40]. Whether eukaryotic and bacterial polytopic membrane aspartyl proteases share these similarities as a result of convergent or divergent evolution remains an unresolved question [12,18,40–43].
Signal peptide peptidase: a potential therapeutic target for parasitic and viral infections
Published in Expert Opinion on Therapeutic Targets, 2022
Christopher Schwake, Michael Hyon, Athar H. Chishti
Intramembrane proteases are a group of enzymes that cleave transmembrane proteins within the hydrophobic lipid bilayer of various organelles [1]. Within the past few years, several intramembrane cleaving proteases (I-CLIPs) have been recognized and categorized by their mode of catalysis: metalloprotease, serine protease, glutamyl protease, and aspartic protease mechanisms [2]. This family includes the site-2-protease, the presenilins, and the SPPs (signal peptide peptidase) [3,4]. The serendipitous discovery of SPP originated during the characterization of a similar aspartyl protease termed presenilin [5,6]. The presenilins contain an intramembrane active site and hydrolyze embedded type I transmembrane proteins [7]. The role of presenilins in human disease has been reviewed extensively in the context of Alzheimer’s disease [8,9]. Originally, SPP was identified as a presenilin homolog [5]. Later, SPP was recognized as distinct from presenilin and four different SPP homologues (SPP2a, SPP2b, SPP2c, and SPP3) were subsequently discovered in the human genome [4,6]. Further research identified SPP genes in numerous eukaryotic, prokaryotic, and archaic species suggesting different yet highly conserved evolutionary functional pathways.
What have we learned from past failures of investigational drugs for Alzheimer’s disease?
Published in Expert Opinion on Investigational Drugs, 2021
Bruno P. Imbimbo, Mark Watling
Alzheimer’s disease (AD) is a neurodegenerative disease with a long preclinical phase, which progressively impairs cognition, behavior and functionality. AD accounts for 50–70% of dementia diagnoses [1]. The commoner of the two types of AD is sporadic AD (SAD), which accounts for more than 95% of cases. It is not caused by a specific gene, although genetic risk factors have been identified [2] the most important and well characterized of which is the APOE gene [3]. The other type of AD is quite rare (1–3% of all AD cases) and has a genetic basis. It is called autosomal dominant AD (ADAD) and is caused by mutations in the amyloid precursor protein (APP) or presenilin (PSEN1 and PSEN2) genes. Presenilins are the protease elements of the γ-secretase enzyme complex that is responsible, together with the β-secretase enzyme (BACE1), for the final release of the β-amyloid (Aβ) peptide from APP. ADAD usually occurs at a younger age and presents with neuropathological and biomarker features that are similar, but not identical, to those of SAD [4].