A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.

We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked a congophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples of the delta9 variant, the deletion was not caused by a splice acceptor site mutation.

Susceptibility locus for Alzheimer's disease on chromosome 10.

The apolipoprotein E (APOE) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However, 50 percent of Alzheimer's disease cases do not carry an APOE4 allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD to detect other susceptibility loci. Here we report evidence for an Alzheimer's disease locus on chromosome 10. Our stage one multipoint lod score (logarithm of the odds ratio for linkage/no linkage) of 2.48 (266 sibling pairs) increased to 3.83 in stage 2 (429 sibling pairs) close to D10S1225 (79 centimorgans). This locus modifies risk for Alzheimer's disease independent of APOE genotype.

Molecular characterization of putative modulatory factors in two Spanish families with A1555G deafness.

The aim of this work is to characterize possible modifying factors in 2 large families carrying the A1555G mitochondrial mutation. The heteroplasmy of the mutation, the presence of aminoglycosides, the cosegregation with other mitochondrial mutations, the proposed linkage in chromosome 8 and the association with TRMU and MTO1 genes were studied. None of the mentioned modifying factors were related with the phenotype presentation of A1555G mutation. However, TRMU G28T single nucleotide polymorphism is present in 1 of the studied families.

Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau.

Molecular genetic analysis is revealing the etiologies of Alzheimer's disease (AD) and related dementias. Here we review genetic and molecular biological evidence suggesting that the peptide A beta 42 is central to the etiology of AD. Recent data also suggests that dysfunction in the cytoskeletal protein tau is on the pathway that leads to neurodegeneration and dementia. Tau is produced either indirectly, by A beta 42, or directly, in some forms of frontotemporal dementia by mutations in tau itself. These data support are refine the amyloid cascade hypothesis for AD and suggest that understanding the causes and consequences of tau dysfunction is an important priority for dementia research.

Genetic analysis of the LGI/Epitempin gene family in sporadic and familial lateral temporal lobe epilepsy.

Mutations in the LGI1/Epitempin gene cause autosomal dominant lateral temporal lobe epilepsy (ADLTE), a partial epilepsy characterized by the presence of auditory seizures. However, not all the pedigrees with a phenotype consistent with ADLTE show mutations in LGI1/Epitempin, or evidence for linkage to the 10q24 locus. Other authors as well as ourselves have found an internal repeat (EPTP, pfam# PF03736) that allowed the identification of three other genes sharing a sequence and structural similarity with LGI1/Epitempin. In this work, we present the sequencing of these genes in a set of ADLTE families without mutations in both LGI1/Epitempin and sporadic cases. No analyzed polymorphisms modified susceptibility in either the familial or sporadic forms of this partial epilepsy.

Genetics of Alzheimer's disease.

Mutations in any one of three genes can cause autosomal dominant, early-onset Alzheimer's disease: these genes are the amyloid precursor protein (APP) gene on chromosome 21, the presenilin-1 (PS-1) gene on chromosome 14 and the presenilin-2 (PS-2) gene on chromosome 1. Pathogenic mutations at all these loci cause mismetabolism of APP such that more of the peptide A beta 42 is produced. This peptide is deposited in the plaques in the brains of Alzheimer's patients. These facts have led to the dominant hypothesis for the disease process: the 'amyloid cascade hypothesis', which proposes that overproduction or failure to clear the peptide A beta 42 is always central to the disease. Genetic variability at the apoliprotein E locus is a major determinant of late onset Alzheimer's disease. The mechanism by which apoliprotein E is involved in the pathogenesis of Alzheimer's disease is not yet known. There are likely to be other genetic factors which impinge on Alzheimer's disease.

Identification and characterization of a novel human brain-specific gene, homologous to S. scrofa tmp83.5, in the chromosome 10q24 critical region for temporal lobe epilepsy and spastic paraplegia.

We describe the structure, genomic organization, and some transcription features of a human brain-specific gene previously localized to the genomic region involved in temporal lobe epilepsy and spastic paraplegia on chromosome 10q24. The gene, which consists of six exons disseminated over 16 kb of genomic DNA, is highly homologous to the porcine tmp83.5 gene and encodes a putative transmembrane protein of 141 amino acids. Unlike its porcine homolog, from which two mRNAs with different 5'-sequences are transcribed, the human gene apparently encodes three mRNA species with 3'-untranslated regions of different sizes. Mutation analysis of its coding sequence in families affected with temporal lobe epilepsy or spastic paraplegia linked to 10q24 do not support the involvement of this gene in either diseases.

Chondroitinases release acetylcholinesterase from chick skeletal muscle.

Bacterial chondroitinases (both ABC and AC types) release asymmetric and globular forms of AChE from chick skeletal muscle samples. Heparinases, however, including heparitinase I, fail to do so under different incubation conditions. These results do not support the direct implication of the heparin/heparan sulfate family of GAGs in the interaction of the different AChE molecular forms with the muscle ECM. GAGs of the chondroitin/dermatan sulfate group could however be involved, either directly or indirectly, in the attachment of the AChE collagen-like tail to the muscle basal lamina.

The genetic and pathological classification of familial frontotemporal dementia.

BACKGROUND: Frontotemporal dementia (FTD) is an important cause of neurodegenerative dementia, particularly in younger patients. TAU has been identified as the gene responsible for FTD linked to chromosome 17, but it is likely that there is pathological and genetic heterogeneity among families with FTD. OBJECTIVE: To explore the genetic and pathological basis of familial FTD. DESIGN: Clinical case series with genetic analysis of each family, and pathological confirmation of diagnosis where possible. SETTING: Specialist dementia research group, particularly recruiting patients with young-onset dementia. PATIENTS: Twenty-two families with an index member with FTD, meeting Lund-Manchester criteria, and a family history of other affected members with dementia were ascertained. RESULTS: Half of the families had mutations in the TAU gene (TAU exon 10 +14, +16, and P301S), and pathological diagnoses were available in 17 of 22 families. Three main pathological diagnoses were made: FTD with neuronal and glial tau deposition, FTD with ubiquitin inclusions, and FTD with neuronal loss and spongiosis but without intracellular inclusions. No cases of familial Pick disease were identified. With the use of the pathological diagnoses, each family with FTD with neuronal and glial tau deposition had a TAU mutation, whereas TAU mutations were not identified in families in the other 2 diagnostic groups. CONCLUSIONS: This study illustrates the value of TAU sequencing in FTD and suggests that around one half of individuals with familial FTD have TAU mutations and dementia with tau pathological findings. Furthermore, these data suggest that there are at least 2 additional genes to be identified among families with autosomal dominant FTD.

The tau gene A0 allele and progressive supranuclear palsy.

BACKGROUND: Recent studies have shown an association between a polymorphic tandem repeat allele, located in intron 9, of the tau gene and progressive supranuclear palsy (PSP). OBJECTIVE: To investigate this tau polymorphism in individuals with a clinical diagnosis of sporadic or familial PSP as well as in cases confirmed by pathology. METHODS: We analyzed the frequency of tau intronic polymorphism, the presence of linkage in two families with multiple cases of PSP, the splicing of exon 10, and direct sequence of the tau gene. RESULTS: We found that patients with a clinical diagnosis of sporadic or familial PSP and individuals with PSP confirmed by neuropathology have greater prevalence of the A0 allele and A0/A0 genotype than controls. This finding, however, was also true for asymptomatic relatives of individuals with PSP. Linkage analysis in familial PSP excluded the location of the gene in the region 17q21. Furthermore, no significant differences were found in the level of expression of exon 10 in PSP, A0/A0 brain with respect to Alzheimer A3/A3 brain. We found no mutations in the tau gene in individuals with familial PSP. CONCLUSIONS: A mutation in the tau gene was not the primary cause of familial PSP. The role of tau and the tau A0 allele in white PSP patients remains unknown, although it may represent a genetic risk factor for several neurodegenerative disorders.

Prevalence of Alzheimer's disease in very elderly people: a prospective neuropathological study.

BACKGROUND: No previous autopsy-controlled, prospective, and population-based studies are available on the prevalence of AD in very elderly people. OBJECTIVE: To study the point prevalence of neuropathologically defined AD in a population of people at least 85 years of age, stratified according to their APOE genotype. METHODS: A population-based sample of 532 (of a total population of 601) elderly Finnish individuals, aged 85 years or more, were clinically tested for dementia in 1991 (with follow-up studies of the survivors in 1994, 1996, and 1999) and genotyped for APOE. An autopsy involving neuropathologic diagnosis of AD according to modified consensus criteria was performed in 118 of 198 deceased subjects who had been demented on April 1, 1991, and in 62 of 201 nondemented individuals. RESULTS: The prevalence of neuropathologically defined AD was 33%, whereas the prevalence of clinically diagnosed AD was 16%. There was a highly significant (p < 0.001) association between the APOE epsilon4 allele and AD: Sixty-three percent of APOE epsilon4 carriers and 20% of noncarriers had neuropathologic AD. The respective figures in subjects aged 90 years or more were 71 and 22%. CONCLUSIONS: The prevalence of neuropathologically defined AD is higher than that reported in most previous studies based on clinical diagnosis. The discrepancy between the neuropathologic and clinical diagnoses of AD in very elderly subjects may affect the results of population-based studies. The APOE genotype has a strong effect on the prevalence of neuropathologically defined AD, even after 90 years of age.

Neurodegenerative diseases of Guam: analysis of TAU.

Mutations in the tau gene have been described in families affected by frontotemporal dementia with parkinsonism linked to chromosome 17. The authors performed a genetic and biochemical analysis of this gene and its product in the parkinsonism dementia complex of Guam, a disorder characterized by the extensive formation of neurofibrillary tangles. The tau gene is not a primary cause of the parkinsonism dementia complex of Guam.

Contribution of APOE promoter polymorphisms to Alzheimer's disease risk.

OBJECTIVE: To determine whether the effects of APOE promoter polymorphisms on AD are independent of the APOE-epsilon4 allele. BACKGROUND: Recently, the -491 A-->T and -219 G-->T polymorphisms located in the APOE promoter have been suggested to be risk factors for AD. However, the effects of these polymorphisms have not always been reproduced in case-control studies, possibly because of the strong linkage disequilibrium existing at this locus or the characteristics of the populations studied. METHODS: Data collection was performed from six independent samples (1,732 patients with AD and 1,926 control subjects) genotyped for APOE exon 4 and the two APOE promoter polymorphisms. The risks associated with the APOE polymorphisms for developing AD were estimated using logistic regression procedures and calculation of odds ratios with 95% CI adjusted by age, sex, and collection center. Independence of the APOE promoter polymorphisms was tested by stratification for APOE-epsilon4 and tertile design was used for age stratification. RESULTS: The independence of the -491 AA genotype was observed in the whole sample whereas the independence of the -219 TT genotype was observed only in the oldest population. CONCLUSION: The -491 and -219 APOE promoter polymorphisms incur risk for AD in addition to risk associated with the APOE-epsilon4 allele, with age accentuating the effect of the -219 TT genotype. Because these polymorphisms appear to influence apoE levels, these results suggest that APOE expression is an important determinant of AD pathogenesis.

Alzheimer's disease presenilin-1 exon 9 deletion and L250S mutations sensitize SH-SY5Y neuroblastoma cells to hyperosmotic stress-induced apoptosis.

Mutations in the presenilin-1 (PS1) and presenilin-2 (PS2) genes account for the majority of early-onset familial Alzheimer's disease cases. Recent studies suggest that presenilin gene mutations predispose cells to apoptosis by mechanisms involving altered calcium homeostasis and oxidative damage. In the present study, we determined whether PS1 mutations also sensitize cells to hyperosmotic stress-induced apoptosis. For this, we established SH-SY5Y neuroblastoma cell lines stably transfected with wild-type PS1 or either the PS1 exon 9 deletion (deltaE9) or PS1 L250S mutants. Cultured cells were exposed to an overnight (17 h) serum deprivation, followed by a 30 min treatment with either 20 mM glucose, 10 nM insulin-like growth factor-1 or 20 mM glucose + 10 nM insulin-like growth factor-1. Cells were then cultured for a further 3, 6 or 24 h and stained for apoptotic condensed nuclei using propidium iodide. Confirmation that cells were undergoing an active apoptotic process was achieved by labelling of DNA strand breaks using the terminal dUTP nick end labelling (TUNEL) technique. We also determined cell viability using 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. Propidium iodide staining revealed that all cell lines and controls showed an increased number of apoptotic cells appearing with condensed nuclei at 24 h compared with 6 h and 3 h. High glucose-induced hyperosmotic stress resulted in significantly more apoptotic cells in the PS1 deltaE9 and PS1 L250S mutation cell lines at 24 h, compared with the wild-type PS1 lines (P < 0.001, ANOVA for both comparisons). Mean values (+/-S.D.) for the percentage number of apoptotic cells at 24 h following high glucose treatment were 16.1 +/- 3.5%, 26.7 +/- 5.5% and 31.0 +/- 5.7% for the wild-type PS1, PS1 deltaE9 and PS1 L250S lines, respectively. The pro-apoptotic effects of high glucose treatment were reversed by 10 nM insulin-like growth factor-1, although to a lesser extent in the mutation cell lines (5.8 +/- 2.4%, 15.2 +/- 7.3% and 13.2 +/- 2.0% for the wild-type PS1, PS1 deltaE9 (P < 0.01 for comparison with wild-type PS1) and PS1 L250S (P < 0.01 for comparison with wild-type PS1) transfected lines, respectively. TUNEL labelling of cells at 24 h following treatment gave essentially the same results pattern as obtained using propidium iodide. The percentage number of apoptotic cells with DNA strand breaks (means +/- S.D.) following high glucose treatment was 15.4 +/- 2.6% for the wild-type PS1, 26.8 +/- 3.2% for the PS1 deltaE9 (P < 0.001 for comparison with wild-type PS1) and 29.7 +/- 6.1% for the PS1 L250S transfected lines (P < 0.001 for comparison with wild-type PS1). The PS1 deltaE9 and PS1 L250S transfected lines also showed a higher number of apoptotic cells with DNA strand breaks at 24 h following high glucose plus insulin-like growth factor-1 treatment (11.4 +/- 2.0% and 14.3 +/- 2.8%, respectively), compared with values for the wild-type PS1 lines (8.5 +/- 2.4%). These differences were significant (P < 0.01) for the comparison of wild-type PS1 and PS1 L250S, but not PS1 deltaE9 lines. The mutation-related increases in number of apoptotic cells at 24 h following high glucose treatment were not accompanied by significant differences in cell viability at this time-point. Our results indicate that PS1 mutations predispose to hyperosmotic stress-induced apoptosis and that the anti-apoptotic effects of insulin-like growth factor-1 are compromised by these mutations. Perturbations of insulin-like growth factor-1 signalling may be involved in PS1 mutation-related apoptotic neuronal cell death in Alzheimer's disease.

Evidence for apolipoprotein E epsilon 4 association in early-onset Alzheimer's patients with late-onset relatives.

Recently several reports have extended the apolipoprotein E (APOE) epsilon 4 association found in late-onset Alzheimer's disease (LOAD) patients to early-onset (EO) AD patients. We have studied this question in a large population of 119 EOAD patients (onset < or = 60 years) in which family history was carefully assessed and in 109 controls. We show that the APOE epsilon 4 allele frequency is increased only in the subset of patients who belong to families where LOAD secondary cases are present. Our sampling scheme permits us to demonstrate that for an individual, bearing at least one epsilon 4 allele increases both the risk of AD before age 60 and the probability of belonging to a family with late-onset affected subjects. Our results suggest that a subset of EOAD cases shares a common determinism with LOAD cases.

Exclusion of genetic linkage to 4q21-23 and 17q21 in a family with Lewy body parkinsonism.

Genetic analysis of markers from chromosomes 4q21-23 and 17q21 in a family with apparently autosomal dominant Lewy body parkinsonism is presented. This analysis shows that the locus leading to this disease is not allelic with that previously shown to lead to Lewy body parkinsonism on chromosome 4 or to the locus on chromosome 17 leading to frontotemporal dementia with parkinsonism. A brief clinical comparison of this family with families showing linkage to these loci is presented. The data suggest that at least one other major genetic determinant for Lewy body parkinsonism remains to be identified.

Cloning and characterization of the presenilin-2 gene promoter.

Mutations in the presenilin-2 (PS-2) have been shown to cause early onset Alzheimer's disease (AD) in a series of families known as the Volga Germans and in an unrelated Italian kindred. Expression of the PS-2 gene is regulated during AD, aging, development and brain injury. Although expressed primarily in neurons, enhanced levels of PS-2 have been reported in astrocytes activated by neuronal damage. Understanding the regulation of the PS-2 gene may thus provide an insight into its role in AD. We have isolated a 3635 bp DNA fragment that contains 2934 bp of DNA sequence upstream from the PS-2 gene. Primer extension analysis was used to map three major transcriptional start sites within the PS-2 gene. The promoter sequence, upstream of each transcriptional start site, does not contain TATA or CAAT boxes but does contain several GC rich sites (Sp-1 and AP-2). A reporter gene construct containing the PS-2 promoter (PS2P, -2934 to +702) transfected into M17 cells drives basal transcription to 20% of the levels of the SV-40 viral promoter. Addition of NGF to PC-12 cells was found to upregulate the PS2P promoter and an NGF-responsive element was localized by deletional analysis between -403 and +13 within the promoter. Since the PS-2 gene has multiple start sites and the upstream sequence is GC rich with no TATA box, the PS-2 promoter is consistent with the GC class of 'housekeeping' genes.

A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene.

A series of mutations has been reported in the presenilin-1 (PS-1) gene which cause early onset Alzheimer's disease (AD). The mutations reported to date have encoded missense mutations which alter residues conserved between PS-1 and the presenilin-2 (PS-2) gene. We have recently determined the intron/exon structure of the PS-1 gene and this information has been used to identify a mutation in the splice acceptor site for exon 9 in a family with early onset AD. Amplification of cDNA from lymphoblasts of affected individuals revealed that the effect of the mutation was to cause splicing out of exon 9, however it does not change the open reading frame of the mRNA. The importance of this observation is discussed.