Light and Electron Microscopic Localization of Presenilin-1 in Primate Brain (original) (raw)
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Brain Expression of Presenilins in Sporadic and Early-onset, Familial Alzheimer’s Disease
Molecular Medicine, 2000
Background: Mutations in the presenilin proteins cause early-onset, familial Alzheimer's disease (FAD). Materials and Methods: We characterized the cellular localization and endoproteolysis of presenilin 2 (PS2) and presenilin 1 (PS1) in brains from 25 individuals with presenilin-mutations causing FAD, as well as neurologically normal individuals and individuals with sporadic Alzheimer's disease (AD). Results: Amino-terminal antibodies to both presenilins predominantly decorated large neurons. Regional differences between the broad distributions of the two presenilins were greatest in the cerebellum, where most Purkinje cells showed high levels of only PS2 immunoreactivity. PS2 endoproteolysis in brain yielded multiple amino-terminal fragments similar in size to the PS1 amino-terminal fragments detected in brain. In addition, two different PS2 amino-terminal antibodies also detected a prominent 42 kDa band that may represent a novel PS2 form in human brain. Similar to PS1 findings, neither amino-terminal nor antiloop PS2 antibodies revealed substantial full-length PS2 in brain. Immunocytochemical examination of brains from individuals with the N 141 I PS2 mutation or eight different PS1 mutations, spanning the molecule from the second transmembrane domain to the large cytoplasmic loop domain, revealed immunodecoration of no senile plaques and only neurofibrillary tangles in the M 139 I PS1 mutation stained with PS1 antibodies. Conclusions: Overall presenilin expression and the relative abundance of full-length and amino-terminal fragments in presenilin FAD cases were similar to control cases and sporadic AD cases. Thus, accumulation of full-length protein or other gross mismetabolism of neither PS2 nor PS1 is a consequence of the FAD mutations examined.
Immunohistochemical analysis of presenilin-1 expression in the mouse brain
FEBS Letters, 1996
At least 22 different mutations associated with earlyonset familial Alzheimer's disease (AD) in various kindreds have been reported to occur in a recently identified gene on chromosome 14, presenilin 1 (PS-1) (Sherrington et al. (1995) Nature 375, 754-760 [1] and reviewed by Van Broeckhoven (1995) Nat. Genet. 11, 230-231 [2]
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.
Different effects of Alzheimer-associated mutations of presenilin 1 on its processing
Neuroscience Letters, 1997
Presenilin 1 (PS 1) shows missense mutations in most early-onset familial Alzheimer's disease (FAD). Transfection of cDNA for wild type PS 1 into rat pheochromocytoma PC12 cells generated a 47 kDa full-size PS 1 protein, which was processed into a 28 kDa N-terminal fragment and a 19 kDa C-terminal fragment. We prepared selected Alzheimer-associated mutations (Gly384Ala, Leu392Val, and Cys410Tyr) of PS 1, which localized after a possible cleavage site. By transient expression in PC12 cells and rat glioma cell line, C6, we examined their influence on the processing of PS 1. Cys410Tyr inhibited proteolytic processing of PS 1, while Gly384Ala and Leu392Val did not. Thus, the Alzheimer related mutations can be divided into two groups in terms of their effect on the proteolytic cleavage of PS 1.
Early-onset Alzheimer's disease with a de novo mutation in the presenilin 1 gene
Experimental Neurology, 2007
A 32-year-old woman diagnosed with very rapidly progressing early-onset Alzheimer's disease (EOAD), age of onset 29 years, and S170F mutation in presenilin 1 gene (PSEN1) is presented. Neuroimaging conducted 2 years after the first symptoms was typical for the advanced stage of Alzheimer's disease (AD), showing cortical brain atrophy, particularly within hippocampus, frontal and temporal cortex. The unaffected parents of the proband are not carriers of the mutation. The paternity was confirmed by microsatellite typing, strongly suggesting de novo origin of S170F mutation. In silico modeling of S170F mutation impact on presenilin 1 (PS1) transmembrane structure indicates that the mutation considerably alters putative interactions of PS1 with other proteins within γ-secretase complex.
In situ hybridization analysis of presenilin 1 mRNA in Alzheimer disease and in lesioned rat brain
Proceedings of the National Academy of Sciences, 1996
Presenilin-1 (PS-1) gene mutations are responsible for the majority of the early onset familial forms of Alzheimer disease (AD). Neither PS-1's anatomic distribution in brain nor expression in AD have been reported. Using in situ hybridization in the rat forebrain, we show that PS-1 mRNA expression is primarily in cortical and hippocampal neurons, with less expression in subcortical structures, in a regional pattern similar to APP695. Excitotoxic lesions lead to loss of PS-1 signal. A neuronal pattern of expression of PS-1 mRNA was also observed in the human hippocampal formation. AD and control levels did not differ. PS-1 is expressed in brain areas vulnerable to AD changes more so than in areas spared in AD; however, PS-1 expression is not sufficient to mark vulnerable regions. Collectively, these data suggest that the neuropathogenic process consequent to PS-1 mutations begins in neuronal cell populations.
Presenilin structure, function and role in Alzheimer disease
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2000
Numerous missense mutations in the presenilins are associated with the autosomal dominant form of familial Alzheimer disease. Presenilin genes encode polytopic transmembrane proteins, which are processed by proteolytic cleavage and form high-molecular-weight complexes under physiological conditions. The presenilins have been suggested to be functionally involved in developmental morphogenesis, unfolded protein responses and processing of selected proteins including the L-amyloid precursor protein. Although the underlying mechanism by which presenilin mutations lead to development of Alzheimer disease remains elusive, one consistent mutational effect is an overproduction of long-tailed amyloid L-peptides. Furthermore, presenilins interact with L-catenin to form presenilin complexes, and the physiological and mutational effects are also observed in the catenin signal transduction pathway.
The Presenilins and Alzheimer's Disease
Human molecular genetics, 1997
The presenilin 1 and presenilin 2 genes have been identified as pathogenic loci involved in the majority of early onset, autosomal dominant Alzheimer's disease. A series of (predominantly) missense mutations have been identified in the two genes which lead to disease. The ...
Brain Research, 1997
Missense mutations of presenilin 1 (PS-1) and presenilin 2 (PS-2) genes cause the majority of early-onset familial forms of Alzheimer's disease (AD). We previously characterized the distribution of the PS-1 protein in the mouse brain by immunohistochemistry using an antibody directed against an epitope located in the large hydrophilic loop [Moussaoui, S., Czech, C., Pradier, L., Blanchard, V., Bonici, B., Gohin, M., Imperato, A. and Revah, F., Immunohistochemical analysis of presenilin 1 expression in the mouse brain, FEBS Lett., 383 (1996) 219-222]. Similarly, we now report the distribution pattern of PS-2 protein in the mouse brain. For these experiments we used a polyclonal antibody raised against a synthetic peptide corresponding to the amino-acid sequence 7-24 of the predicted human PS-2 protein. The specificity of the antibody was evidenced by its ability to recognize PS-2 protein in immunoprecipitation studies and by antigen-peptide competition. In the mouse brain, PS-2 protein was present in numerous cerebral structures, but its distribution in these structures did not correlate with their susceptibility to AD pathology. In all examined structures of the gray matter, PS-2 protein was concentrated in neuronal cell bodies but it was not detected in the glial cells of the white matter. The regional distribution pattern of PS-2 protein was almost identical to that of PS-1 protein. Moreover, PS-2 protein co-localized with PS-1 protein in a large number of neuronal cell bodies. In terms of subcellular localization, PS-2 immunostaining was present almost exclusively in neuronal cell bodies while PS-1 immunostaining was also present in dendrites. This could be explained by the different epitopes of the antibodies and the known proteolytic processing of both presenilins in vivo [Tanzi, R.E., Kovacs, D.M., Kim, T.-W., Moir, R.D., Guenette, S.Y. and Wasco, W., The presenilin genes and their role in early-onset familial Alzheimer's disease, Alzheimer's disease Rev., 1 (1996) 91-98]. Within neuronal cell bodies, the immunostaining of PS-2 protein, as well as that of PS-1 protein, had a reticular and granular appearance. This suggests in agreement with previous observations on PS-1 and PS-2 in COS and H4 cells [Kovacs, D.M., Fausett, H.J., Page, K.J., Kim, T.-W., Moir, R.D., Merriam, D.E., Hollister, R.D., Hallmark, O.G., Mancini, R., Felsenstein, K.M., Hyman, B.T., Tanzi, R.E., Wasco, W., Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells, Nature Med., 2 (1996) 224-229] that these proteins are situated in intracytoplasmic organelles, possibly the endoplasmic reticulum and the Golgi complex.