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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).
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.
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
Early symptoms in the preclinical phase can be suspected by applying the criteria to patients with subtle features, and this sensitization may be useful when treatment options become available, although tools are arbitrary. How ethical and how early are questions to be answered with reference to genetics? Three proteases, α, β and γ, process amyloid precursor protein. When acted upon by β-secretase, Aβ is generated, which is pathogenic. Presenilin-1 and -2 are involved in familial AD. The insoluble Aβ causes senile plaques. Tau hyperphosphorylation causes neurofibrillary tangles. In isolation, allele APOEε4 cannot produce AD, but, when there is vascular compromise, trauma, anesthetic events, or excitotoxicity, interaction with Aβ leads to pathogenicity (Jack et al. 1999).
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].
The CB2 cannabinoid receptor as a therapeutic target in the central nervous system
Published in Expert Opinion on Therapeutic Targets, 2021
David Cabañero, Elena Martín-García, Rafael Maldonado
CB2rs were postulated as possible modulators of the inflammatory response associated with the neurodegenerative process of Alzheimer’s disease and as a possible target for new therapeutic approaches. A pioneering study revealed that CB2rs were associated with this disease by demonstrating their presence in activated microglial cells surrounding the neuritic plaques in postmortem tissue from patients [93]. Further studies revealed that CB2r activation by the selective agonist MDA7 showed protective effects in a mouse model of Alzheimer’s disease overexpressing amyloid-beta precursor protein and presenilin-1. The effects of the CB2r agonist were revealed by the reduction of hippocampal microglial inflammation and plasticity, the increase of beta-amyloid clearance, and the amelioration of glutamatergic signaling and memory performance [94]. The CB2r agonist 1-phenylisatin also improved learning and memory and reduced hippocampal beta-amyloid plaques in a mouse model of Alzheimer’s disease induced by intracerebroventricular administration of streptozotocin and aluminum trichloride [95]. In agreement, a genetic mouse model of Alzheimer’s disease with five familial Alzheimer’s disease mutations showed enhanced CB2rs levels in the CNS at 3 months of age, which correlated with inflammation markers and beta-amyloid plaques in cortex and hippocampus [96]. Similarly, postmortem brain analysis of patients with Alzheimer’s disease showed CB2r upregulation in the cortex, positively correlated with amyloid-beta levels and the number of senile plaques [97].
Cardiac adenovirus-associated viral Presenilin 1 gene delivery protects the left ventricular function of the heart via regulating RyR2 function in post-ischaemic heart failure
Published in Journal of Drug Targeting, 2018
Tian Li, Yafeng Shen, Li Su, Xiaoyan Fan, Fangxing Lin, Xuting Ye, Dianer Ding, Ying Tang, Yongji Yang, Changhai Lei, Shi Hu
Presenilin-1 (PSEN1) is a transmembrane protein that has been detected in the brain and is also strongly expressed in the heart. It is a part of the gamma-secretase protease complex and is a novel gene of causative genes related to familial Alzheimer's disease. Moreover, gene mutations of PSEN1 were detected in nearly 1% (3/235) of patients with idiopathic dilated cardiomyopathy [9]. Interestingly, the expression of the PSEN1 mutant in hippocampal cells has been shown to increase ER Ca2+ levels and enhance the susceptibility to induced Ca2+ release in a mouse model [10]. These cells also showed alterations in the ER RyR levels. Given this potent modulation of RyR by PSEN1 proteins, the question arises as to whether PSEN1 expression may restore normal intracellular Ca2+ homeostasis by facilitating the expression and function of RyR in the pathogenesis of HF disease.