Genetics of Alzheimer’s Disease: An Insight Into Presenilins and Apolipoprotein E Instigated Neurodegeneration (original) (raw)
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Archives of Pharmacal Research, 2006
Mutation in the presenilin 2 (PS2mt) is known to be one of factors involved in the development of Alzheimer's disease (AD). It was recently revealed that an abnormality of lipid metabolism is a phenomenon occurring in AD. Therefore, the aim of this study was to investigate the potential relationship between the mutation of PS2 and alterations of the lipid profile within the brain. The results showed there increases in the levels of cholesterol, low density lipoprotein and triglyceride, but a decrease in the level of high density lipoprotein in brain tissues expressing mutant PS2. These findings indicated that PS2mt is involved in the abnormalities of the lipid profile, which could cause or result in the development of AD.
Human Mutation, 2006
The varied ways in which mutations in presenilins (PSEN1 and PSEN2) affect amyloid β precursor protein (APP) processing in causing early-onset familial Alzheimer disease (FAD) are complex and not yet properly understood. Nonetheless, one useful diagnostic marker is an increased ratio of Aβ42 to Aβ40 (Aβ42/Aβ40) in patients' brain and biological fluids as well as in transgenic mice and cells. We studied Aβ and APP processing for a set of nine clinical PSEN mutations on a novel and highly reproducible ELISA-based in vitro method and also sought correlation with brain Aβ analyzed by image densitometry and mass spectrometry. All mutations significantly increased Aβ42/Aβ40 in vitro by significantly decreasing Aβ40 with accumulation of APP C-terminal fragments, a sign of decreased PSEN activity. Only for half of the mutations tested, a significant increase in absolute levels of Aβ42 was observed. We also showed that age-of-onset of PSEN1-linked FAD correlated inversely with Aβ42/Aβ40 (r = -0.89; P = 0.001) and absolute levels of Aβ42 (r = -0.83; P = 0.006), but directly with Aβ40 levels (r = 0.69; P = 0.035). These changes also partly correlated with brain Aβ42 and Aβ40 levels. Together our data suggested that Aβ40 might be protective by perhaps sequestering the more toxic Aβ42 and facilitating its clearance. Also, the in vitro method we described here is a valid tool for assaying the pathogenic potential of clinical PSEN mutations in a molecular diagnostic setting.
Electrica, 2018
Alzheimer's disease (AD) is a neurodegenerative disease and is identified by the detection of amyloid-plaques and neurofibrillary tangles in the brain. Amyloid precursor protein gene, presenilin 1 (PSEN1) gene, and presenilin 2 (PSEN2) gene are responsible for this disease. PSEN2 and amyloid precursor protein (APP) gene mutations are a much rarer cause of familial AD patients. This study aims to clone the PSEN2 gene and create vectors with different mutations by directed mutagenesis. As a result of the experiments, the PSEN2 cDNA was cloned between the BamHI and KpnI cutoff points of the pBluescript II sk (+) vector. PSEN1 and PSEN2 homologs have a role in cell destiny decision and AD progress. We studied some of the PSEN2 mutations (Ala252Thr and Pro334Arg) and provided expression analysis in eukaryotic cell cultures. Amyloid β-protein (Aβ), which is produced by endoproteolytic cleavage of the APP, is considered to play a role in AD. While nominal concentration of Aβ40 is 10 times of Aβ42, the last peptide is firmly linked to AD pathogenesis. Amyloid β-protein is generated by the γ-secretase cleavage of APP onset and the progression of AD, and it is the primary ingredient of the senile plaques. The Aβ42 dodecamer plays a central role in AD. In future studies, it will be determined if there is an increase in Aβ42 protein levels, and the effect on this early onset AD can be identified.
Presenilin-1 protein expression in familial and sporadic Alzheimer's disease
Annals of Neurology, 1997
Mutations of the presenilin PSI and PS2 genes are closely linked to aggressive forms of early-onset (<60 years) familial Alzheimer's disease. A highly specific monoclonal antibody was developed to identify and characterize the native PSI protein. Western blot analyses revealed a predominant 32-kd immunoreactive polypeptide in a variety of samples, including PC12 cells transfected with human PSI complementary DNA, brain biopsy specimens from demented patients, and postmortem samples of frontal neocortex from early-onset familial Alzheimer's disease cases (PSI and PS2), lateonset sporadic Alzheimer's disease cases, and cases of other degenerative disorders. This truncated polypeptide contains the N-terminus of PS1 and appeared unchanged across cases. In 2 early-onset cases linked to missense mutations in the PSI gene, a PSI immunoreactive protein (-49 kd) accumulated in the frontal cortex. This protein was similar in size to full-length PSI protein present in transfected cells overexpressing PSI complementary DNA, and in lymphocytes from an affected individual with a deletion of exon 9 of the PSI gene, suggesting that mutations of the PSI gene perturb the endoproteolytic processing of the protein. Immunohistochemical studies of control brains revealed that PS 1 is expressed primarily in neurons, with the protein localized in the soma and dendritic processes. In contrast, PSI showed striking localization to the neuropathology in early-onset familial Alzheimer's disease and sporadic Alzheimer's disease cases. PSI immunoreactivity was present in the neuritic component of senile plaques as well as in neurofibrillary tangles. Localization of PSI immunoreactivity in familial and sporadic Alzheimer's disease suggests that genetically heterogeneous forms of the disease share a common pathophysiology involving PSI protein. EJ. Presenilin-1 protein expression in familial and sporadic Alzheimer's disease. Ann Neurol 1997;4 1:742-753 _ _ _ _ _ _~. Alzheimer's disease (AD) is heterogeneous, with several distinct genes linked to familial (FAD) and sporadic forms of the disorder. The apolipoprotein E (Apo E) ~4 allele is a well-established risk factor for late-onset FAD, as well as for the more commonly occurring sporadic forms [ 11. Early-onset FAD accounts for about 5 to 10% of all cases, and is notable clinically for a highly aggressive nature with earlier age at onset (typically <60 years), shorter duration of survival, and more prominent myoclonus, seizures, and aphasia 12-71. The pathological features of FAD are similar to those of sporadic AD with abundant amyloid plaques and neurofibrillary tangles [G, 71. The autosomal dominant patterns of inheritance of the early-onset forms have enabled identification of three distinct genes linked to the disease, including tht. amyloid precursor protein (APP) gene on chromosome 21 [S-lO], presenilin-1 (PSI, origiiially termed S182) on chromo-some 14 [l l-151, and presenilin-2 (PS2, originally termed STM2 or E5-1) on chromosome 1 [15-171.
Genetics of early-onset Alzheimer dementia
TheScientificWorldJournal, 2003
Alzheimer's dementia (AD) is the most common degenerative disorder of the central nervous system. Although the onset of dementia is above 65 years of age in the majority of the patients (late-onset AD, LOAD), a small subgroup of patients develops AD before 65 years of age (early-onset AD, EOAD). To date 3 genes responsible for EOAD have been identified: the amyloid precursor protein gene (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). PSEN1 is the most frequently mutated EOAD gene with a mutation frequency of 18 to 50% in autosomal dominant EOAD. In addition, the epsilon4 allele of the gene encoding apolipoprotein E (APOE) was identified as a risk factor for both LOAD and EOAD. Many studies reported other susceptibility genes, but the APOEepsilon4 alelle has been the only risk factor that was consistently replicated in all AD populations. Extensive cell biology research in the past ten years led to the hypothesis that the 4 EOAD genes lead to AD through a common biological...
Alzheimer's & Dementia, 2014
Background: Early-onset familial Alzheimer disease (AD) is an autosomal dominant disorder caused by mutations in the amyloid precursor protein, presenilin 1 (PSEN1), or presenilin 2 gene. The objective of this study was to characterize the phenotype in a large family with a PSEN1 F177S mutation by performing detailed clinical assessments, neuroimaging, and neuropathological analysis. Methods: In two subjects, clinical and neuropsychological assessments, structural magnetic resonance imaging, F-18-2-fluoro-2-deoxy-D-glucose positron emission tomographic imaging, AD biomarkers in cerebrospinal fluid and genetic analysis were available. In three deceased affected subjects, medical records were reviewed. In one subject, a complete neuropathological examination was available. Results: Cognitive impairment and neurological symptoms developed homogeneously around 30 years of age and worsened rapidly. All subjects died about 7 years (range, 6-8 years) after disease onset before 40 years of age. All technical diagnostic information (neuroimaging, cerebrospinal fluid) were typically for AD. Neuropathology showed abundant neuritic plaques and neurofibrillary tangles, typical of severe AD. Antidementia treatment in one subject did not alter the length of survival. Conclusions: The PSEN1 F177S mutation leads to typical AD starting at age 30 and a homogeneous phenotype with rapid cognitive decline and prominent neurological symptoms. Excessive amyloid beta 42 production in the brain cortex corresponds well with other PSEN1 mutations.
Alzheimer disease: Amyloidogenesis, the presenilins and animal models
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2007
Alzheimer's disease is the most prevalent form of dementia. Neuropathogenesis is proposed to be a result of the accumulation of amyloid beta peptides in the brain together with oxidative stress mechanisms and neuroinflammation. The presenilin proteins are central to the gammasecretase cleavage of the amyloid prescursor protein (APP), releasing the amyloid beta peptide. Point mutations in the presenilin genes lead to cases of familial Alzheimer's Disease by increasing APP cleavage resulting in excess amyloid beta formation. This review discusses the molecular mechanism of Alzheimer's disease with a focus on the presenilin genes. Alternative splicing of transcripts from these genes and how these may function in several disease states is discussed. There is an emphasis on the importance of animal models in elucidating the molecular mechanisms behind the development of Alzheimer's disease and how the zebrafish, Danio rerio, can be used as a model organism for analysis of presenilin function and Alzheimer's disease pathogenesis.