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Epidemiology and subtypes of dementia
Published in Marjolein de Vugt, Janet Carter, Understanding Young Onset Dementia, 2021
Autosomal dominant familial Alzheimer's disease is more common in young patients, whereas sporadic Alzheimer's disease in people under 50 is rare. Mutations and duplications of the amyloid precursor protein (APP), as well as presenilin-1 and presenilin-2 (PSEN1 and PSEN2) genes, are associated with familial Alzheimer's disease (Janssen et al., 2003). Auguste D, the first documented patient with Alzheimer's disease was thought to have a PSEN1 mutation; however, after the original patient notes and histology slides were rediscovered, it was not possible to confirm a genetic mutation (Müller et al., 2013; Rupp et al., 2014). The clinical phenotype is usually similar to that of late onset sporadic Alzheimer's disease with prominent episodic memory impairment. This similarity has supported the generalisability of findings from familial Alzheimer's disease patient groups to the more common sporadic late onset patient group (Scahill et al., 2002). However, some distinct differences remain between sporadic late onset and familial Alzheimer's disease. Familial AD patients generally have early myoclonus, relatively preserved naming and in some cases prominent speech production problems (Godbolt et al., 2004; Ryan & Rossor, 2010). Additionally, the pattern of cerebral atrophy seen on volumetric MRI tends to favour more posterior atrophy with relatively preserved hippocampal volume (Migliaccio et al., 2009).
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).
Central nervous system: Adult-onset and psychiatric disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Alzheimer’s disease is the most common dementia of old age, and increased survival makes it a major problem for society as well as for individual families. Certain diagnosis is only possible at autopsy and rests upon the demonstration of large numbers of senile plaques and neurofibrillary tangles in the brains of those affected. A specific locus on chromosome 21 was suggested by the occurrence of Alzheimer’s disease in older Down syndrome patients, and by the location of the gene encoding β-amyloid precursor protein (the major constituent of the senile plaques) on this chromosome. Specific mutations have now been identified in this gene in a few families showing dominant inheritance of early-onset Alzheimer’s disease, while some others show duplications of APP, but in more families the disease is determined by mutations in the presenilin genes (PSEN1 and PSEN2, on chromosomes 14 and 1, respectively).
Stereotaxic-assisted gene therapy in Alzheimer’s and Parkinson’s diseases: therapeutic potentials and clinical frontiers
Published in Expert Review of Neurotherapeutics, 2022
Samar O. El Ganainy, Tony Cijsouw, Mennatallah A. Ali, Susanne Schoch, Amira Sayed Hanafy
Sporadic, age-related AD is the most common form, but familial, early-onset forms are described as well. Aging is the strongest risk factor for developing AD, followed by genetics and environmental contribution [45]. The frequently encountered genetic mutations correlating to familial AD are found in presenilin (PSEN) 1 and 2, which constitute the catalytic subunit of γ-secretase. PSEN1 mutations lead to increased activation of the γ-secretase complex, which plays an essential role in APP cleavage to form Aβ, thereby significantly increasing the latter’s levels [52]. PSEN2 mutations are less frequent and may affect the Aβ42/Aβ40 ratio by dysregulating γ-secretase activity without increasing Aβ levels [53]. Other rare mutations are found in the APP gene, which interfere with the APP cleavage and Aβ aggregation [54].
The contribution of C. elegans neurogenetics to understanding neurodegenerative diseases
Published in Journal of Neurogenetics, 2020
Joseph J. H. Liang, Issa A. McKinnon, Catharine H. Rankin
In humans, APP is cleaved by several secretases to yield its downstream products, and its products come from two primary cleavage pathways. In the non-amyloidogenic pathway, APP is cleaved first by α-secretase to release extracellular sAPPα. The remaining fragment is then cleaved by the γ-secretase to yield more of its components. In the amyloidogenic pathway, β-secretase first cleaves APP to release the sAPPβ fragment and the remaining fragment is cleaved by γ-secretase to yield Aβ in the extracellular space as one of its components (Figure 1). In C. elegans, no β-secretase activity that cleaves APP has been detected, suggesting that APL-1 is processed by the α/γ-secretase processing pathway. As α-secretase cleavage releases the extracellular fragment and subsequent cleavage with γ-secretase liberates the intracellular domain, more interest lies in the characterization of γ-secretase. Of the four core proteins that make up γ-secretase, presenilins (human PSEN1 and PSEN2) are the most studied due to its proteolytic function. Indeed, pathogenic mutations in PSEN1 account for a majority of cases of fAD (Janssen et al., 2003).
BACE inhibitors in clinical development for the treatment of Alzheimer’s disease
Published in Expert Review of Neurotherapeutics, 2018
Francesco Panza, Madia Lozupone, Vincenzo Solfrizzi, Rodolfo Sardone, Carla Piccininni, Vittorio Dibello, Roberta Stallone, Gianluigi Giannelli, Antonello Bellomo, Antonio Greco, Antonio Daniele, Davide Seripa, Giancarlo Logroscino, Bruno P. Imbimbo
The Aβ peptide is generated by metabolism of amyloid precursor protein (APP), a type I transmembrane glycoprotein formed by 695–770 amino acids. Normally, APP is cleaved close to the membrane by an extracellular protease known as the α-secretase. This liberates a soluble extracellular fragment, sAPPα. Alternatively, APP is cleaved by an aspartyl protease known as β-secretase (or β-site APP cleaving enzyme 1, BACE1) generating a soluble extracellular fragment (sAPPβ) and a cell-membrane-bound fragment (C99). C99 is cleaved within the membrane by an enzymatic complex formed of four proteins (presenilin, nicastrin, anterior pharynx-defective 1 and presenilin enhancer 2), known as γ-secretase. Presenilin is the catalytic subunit of γ-secretase and is encoded by either the PSEN1 or PSEN2 gene. The γ-secretase cleavage releases an intracellular peptide known as amyloid intracellular domain (AICD) and the Aβ peptide. Aβ may have different lengths, the most abundant being of 40 amino acids (Aβ1–40) and the less soluble of 42 amino acids (Aβ1–42). Aβ aggregates to form oligomers, protofibrils, fibrils and ultimately plaques that represent one of the hallmarks of AD pathology.