Alcune pubblicazioni recenti del prof. Sandro Sorbi 

(da PUBMED )

Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease.

Carrieri G, Bonafe M, De Luca M, Rose G, Varcasia O, Bruni A, Maletta R, Nacmias B, Sorbi S, Corsonello F, Feraco E, Andreev KF, Yashin AI, Franceschi C, De Benedictis G.

Department of Cell Biology, University of Calabria, Rende, Italy.

Allele epsilon4 of the nuclear APOE gene is a leading genetic risk factor for sporadic Alzheimer's disease (AD). Moreover, an allele-specific effect of APOE isoforms on neuronal cell oxidative death is known. Because of the role of the mitochondrial genome (mtDNA) in oxidative phosphorylation and oxidative stress, an interaction between APOE polymorphism and mtDNA inherited variability in the genetic susceptibility to sporadic AD can be hypothesized. We have explored this hypothesis by analyzing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE epsilon4 carriers and non-carriers. We found that the frequency distribution of mtDNA haplogroups is different between epsilon4 carriers and non-carriers (P=0.018), thus showing non-random association between APOE and mtDNA polymorphisms. The same analysis, carried out in two samples of healthy subjects (179 age-matched and 210 individuals aged more than 100 years), showed independence between epsilon4 allele and mtDNA haplogroups. Therefore, the APOE/mtDNA interaction is restricted to AD and may affect susceptibility to the disease. In particular, some mtDNA haplogroups (K and U) seem to neutralize the harmful effect of the APOE epsilon4 allele, lowering the epsilon4 odds ratio from statistically significant to non-significant values.

Neurosci Lett 2001 Feb 16;299(1-2):9-12

Alpha2-macroglobulin polymorphisms in Italian sporadic and familial Alzheimer's disease.

Nacmias B, Tedde A, Cellini E, Forleo P, Orlacchio A, Guarnieri BM, Petruzzi C, D'Andrea F, Serio A, Sorbi S.

Department of Neurological and Psychiatric Sciences, University of Florence, Viale Morgagni 85, 50134 Florence, Italy.

A 5-bp deletion and a Val1000 polymorphism at the alpha(2)-macroglobulin (A2M) gene have recently been reported to be associated with late onset Alzheimer's disease (AD). As recently it has been suggested that the effect of the A2M gene on AD susceptibility may be limited to certain populations or families, we analyzed the segregation of A2M and apolipoprotein E polymorphisms in Italian sporadic and familial AD. We analyzed the two polymorphisms in a total of 346 subjects including 98 controls by polymerase chain reaction-restriction fragment length polymorphism method. Our data do not confirm these associations, in particular we found a significant decrease of the deletion allele in AD with respect to controls. Our data do not support a role for the A2M gene as genetic risk factor for AD.

Neurology 2000 Nov 28;55(10):1590-1

A presenilin-1 mutation (Leu392Pro) in a familial AD kindred with psychiatric symptoms at onset.

Tedde A, Forleo P, Nacmias B, Piccini C, Bracco L, Piacentini S, Sorbi S.

Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

Lack of SOD1 gene mutations and activity alterations in two Italian families with amyotrophic lateral sclerosis.

Gestri D, Cecchi C, Tedde A, Latorraca S, Orlacchio A, Grassi E, Massaro AM, Liguri G, St George-Hyslop PH, Sorbi S.

Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder, which results from the degeneration of motor neurons in the brain and spinal cord. Approximately 20% of the inherited autosomal dominant cases are due to mutations within the gene coding for Cu/Zn superoxide dismutase 1 (SOD1), a cytosolic homodimeric enzyme that catalyzes the dismutation of toxic superoxide anion. We investigated the presence of SOD1 gene mutations and activity alterations in two unrelated families of ALS patients from Elba, an island of central Italy. No mutation in SOD1 exon 1 to 5 and no activity alteration were observed in all members of the two analyzed ALS families (FALS). These data show an apparent heterogeneous distribution of ALS patients with SOD1 gene mutations among different populations and suggest that another genetic locus could be involved in the disease

Arch Neurol 2000 Feb;57(2):210-4

Association between angiotensin-converting enzyme and Alzheimer disease.

Farrer LA, Sherbatich T, Keryanov SA, Korovaitseva GI, Rogaeva EA, Petruk S, Premkumar S, Moliaka Y, Song YQ, Pei Y, Sato C, Selezneva ND, Voskresenskaya S, Golimbet V, Sorbi S, Duara R, Gavrilova S, St George-Hyslop PH, Rogaev EI.

Department of Medicine (Genetics Program), Boston University School of Medicine, Mass, USA.

BACKGROUND: Angiotensin-converting enzyme has been reported to show altered activity in patients with neurologic diseases. An insertion-deletion polymorphism in ACE has recently been linked to heart disease, cerebrovascular disease, and AD. OBJECTIVE: To determine whether the angiotensin-converting enzyme (ACE) is associated with risk of Alzheimer disease (AD). METHODS: We investigated the ACE polymorphism as a potential risk factor for AD in 151 patients with AD and 206 ethnically matched controls from Russia and in 236 patients with AD and 169 controls from North America by means of allele association methods and logistic regression. RESULTS: None of the ACE genotypes was associated with increased susceptibility to AD in the total sample or in subsets stratified by apolipoprotein E gene (APOE) epsilon4 status. However, the D allele was more frequent among AD cases between ages 66 and 70 years compared with controls in both the Russian (P = .02) and North American (P = .001) datasets. In this age group, the effect of D (odds ratio, 11.2; 95% confidence interval, 2.9-44.0) appeared to be independent of and equal or greater in magnitude to the effect of APOE epsilon4 (odds ratio, 7.8; 95% confidence interval, 3.5-7.4). CONCLUSIONS: Our results suggest that APOE and ACE genotypes may be independent risk factors for late-onset AD, but the ACE association needs to be confirmed in independent samples in which the time and extent of vascular cofactors can be assessed.

Ann Neurol 1999 Mar;45(3):397-400

HLA A2 allele is associated with age at onset of Alzheimer's disease.

Ballerini C, Nacmias B, Rombola G, Marcon G, Massacesi L, Sorbi S.

Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

The prevalence of the HLA A2 allele was investigated in a group of Italian patients with sporadic and early-onset familial Alzheimer's disease (AD and FAD) to analyze the potential association of this allele with early age of onset of the disease. The possible interaction between the HLA A2 allele and apolipoprotein E epsilon4 allele was analyzed. Our data suggest that A2 and epsilon4 alleles may have additive effects on AD onset, and that A2 may play an important role in determining or contributing to a very early age at onset. These findings further support the hypothesis of the involvement of an immune/inflammatory mechanism in the pathogenesis of AD.

Association between bleomycin hydrolase and Alzheimer's disease in caucasians.

Farrer LA, Abraham CR, Haines JL, Rogaeva EA, Song Y, McGraw WT, Brindle N, Premkumar S, Scott WK, Yamaoka LH, Saunders AM, Roses AD, Auerbach SA, Sorbi S, Duara R, Pericak-Vance MA, St George-Hyslop PH.

Department of Medicine, Boston University School of Medicine, MA 02118, USA.

A recent study showed modest evidence for an increased frequency of the bleomycin hydrolase (BH) V/V genotype in Alzheimer's disease (AD) patients compared with non-demented controls. To test this hypothesis, we examined this polymorphism in 621 rigorously evaluated patients and 502 control subjects (all caucasian) but were unable to detect an association between BH and AD even after controlling for age, gender, and apolipoprotein E (ApoE) genotype. We conclude that this polymorphism does not account for inherited susceptibility to AD in the populations represented in this sample.

Implication of alpha1-antichymotrypsin polymorphism in familial Alzheimer's disease.

Nacmias B, Marcon G, Tedde A, Forleo P, Latorraca S, Piacentini S, Amaducci L, Sorbi S.

Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

A common polymorphism in the alpha1-antichymotrypsin (ACT) gene has been shown to modify the Apolipoprotein E (ApoE) epsilon4-associated Alzheimer's disease (AD) risk identifying the combination of the ACT/AA and ApoE epsilon4/epsilon4 genotypes as a potential susceptibility marker for AD. Using the polymerase chain reaction, we analyzed the segregation of the ACT and ApoE polymorphisms in familial Alzheimer's disease (FAD) patients carrying mutations in Presenilin (PS) and APP genes and in both early onset (EO) and late onset (LO) FAD patients without known mutations. Our data suggest that ACT does not represent an additional risk factor for PS and APP mutated families. However, in LOFAD patients a high frequency of the combined ACT/AA and ApoE epsilon4/epsilon4 genotypes suggest that ACT may interact with ApoE and play a role in LOFAD.

Ann N Y Acad Sci 1997 Sep 26;826:382-5

Inherent abnormalities in oxidative metabolism in Alzheimer's disease: interaction 
with vascular abnormalities.

Blass JP, Sheu KF, Piacentini S, Sorbi S.

Burke Medical Research Institute, Cornell University, White Plains, New York, USA.

Extensive studies over the last 20 years have documented the existence of inherent 
abnormalities in oxidative/energy metabolism in Alzheimer's disease (AD). These abnormalities 
can be linked to characteristics of AD by plausible pathophysiological mechanisms for which 
there is abundant, robust evidence. The inherent abnormalities in cerebral metabolism of oxygen 
and glucose can reasonably be expected to interact synergistically with vascular compromise 
of cerebral oxygen and glucose metabolism in causing brain damage in AD.

Neurosci Lett 1997 Jul 4;229(3):177-80

Analysis of apolipoprotein E, alpha1-antichymotrypsin and presenilin-1 genes polymorphisms in dementia caused by normal pressure hydrocephalus in man.

Nacmias B, Tedde A, Guarnieri BM, Petruzzi C, Ortenzi L, Serio A, Amaducci L, Sorbi S.

Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

Normal pressure hydrocephalus (NPH) is characterized by dementia, gait disorders and urinary incontinence. Apolipoprotein E (ApoE) epsilon4 allele has been associated with severity of dementia in Alzheimer's disease (AD) and in other forms of dementia. Moreover, homozygosity of the A allele of the alpha1-antichymotrypsin (ACT) gene and of allele 1 of the presenilin-1 (PS-1) gene was associated with an increased risk for late onset AD. We analyzed the distribution of ApoE, ACT and PS-1 genotypes and the corresponding allele frequencies in 13 NPH patients. No differences were found in ACT and PS-1 polymorphism distributions in the patients studied with respect to the control group. An increased ApoE epsilon4 allele frequency was observed in NPH patients with respect to controls, thus suggesting that epsilon4 allele may also be involved in the pathogenesis of the disease.

Neurosci Lett 1997 Jan 31;222(2):132-4

Presenilin-1 gene intronic polymorphism in sporadic and familial Alzheimer's disease.

Sorbi S, Nacmias B, Tedde A, Forleo P, Piacentini S, Latorraca S, Amaducci L.

Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

A recent observation has shown a genetic association between an intronic polymorphism in the Presenilin-1 (PS-1) gene and late onset Alzheimer's disease (AD). The homozygosity of the 1 allele in the PS-1 gene was associated with a doubling of the risk for late onset AD. However, contrasting results have been published. We analyzed the distribution of the PS-1 intronic polymorphism in patients with sporadic AD and in seven familial AD (FAD) families carrying pathogenetic mutations in the amyloid precursor protein (APP) and Presenilin (PS-1 and PS-2) genes. Significant differences in PS-1 allele frequencies were observed in the Presenilin genes mutated families but not in late onset AD patients and in APP mutated families.

Apolipoprotein E and alpha1-antichymotrypsin polymorphism in Alzheimer's disease.

Nacmias B, Tedde A, Latorraca S, Piacentini S, Bracco L, Amaducci L, Guarnieri BM, Petruzzi C, Ortenzi L, Sorbi S.

Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

A recent observation has shown that a common polymorphism in the alpha1-antichymotrypsin (ACT) gene modifies the apolipoprotein E (ApoE) epsilon4-associated Alzheimer's disease (AD) risk identifying the combination of the ACT/AA and ApoE epsilon4/epsilon4 genotypes as a potential susceptibility marker for AD. We analyzed the segregation of the ApoE and ACT polymorphism in sporadic and familial AD patients. In none of the sporadic AD patients did we find the combination of the ACT/AA and ApoE epsilon4/epsilon4 genotypes. The frequency of ApoE epsilon4/epsilon4 homozygosity in the AD sample resulted highest for the ACT/ TT genotype (17.6%). Our data fail to confirm any additional association with AD beyond the ApoE epsilon4 allele with any ACT genotype, suggesting that ACT does not represent an additional risk factor for AD.

Neurosci Lett 1996 Apr 26;208(3):216-8

The effect of tetraethylammonium on intracellular calcium concentration in Alzheimer's disease fibroblasts with APP, S182 and E5-1 missense mutations.

Failli P, Tesco G, Ruocco C, Ginestroni A, Amaducci L, Giotti A, Sorbi S.

Department of Pharmacology, University of Florence, Italy.

It has been proposed that the lack of intracellular calcium concentration ([Ca2+]i) increase induced by the potassium channel blocker tetraethylammonium (TEA) in skin fibroblast cell lines identifies patients with both sporadic and familial Alzheimer's disease (AD). In order to verify this hypothesis, the effect of TEA on [Ca2+]i was studied in single fura-2-loaded skin fibroblast cell lines available in the Tissue Bank of the Italian Research Council. Four out of eight familial AD patients (one patient with S182 mutation, one patient with E5-1 mutation and two patients with 717 Val-->Ile APP mutation) and two out of five sporadic AD patients showed a positive response to TEA, whereas five out of 11 control lines were unresponsive. Our data suggest that the absence of the TEA-induced increase in [Ca2+]i in skin fibroblast cell lines does not identify all AD patients.

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Ann N Y Acad Sci 1996 Jan 17;777:260-5

Alzheimer's disease and apolipoprotein E in Italy.

Sorbi S, Nacmias B, Forleo P, Piacentini S, Amaducci L.

Department of Neurological Sciences, University of Florence, Italy.

Recent studies have provided evidence of association of apolipoprotein E (ApoE) epsilon 4 allele and late onset familial and sporadic Alzheimer's disease (AD). Epidemiological studies have established allelic variation at the ApoE locus. We have analyzed the ApoE gene polymorphism in a sample of 416 Italian subjects. Our data confirm a significant association between epsilon 4 allele and sporadic AD. The frequency of epsilon 4 allele in early onset familial AD patients was comparable to control values suggesting that epsilon 4 allele does not represent a risk factor for early onset familial AD (EOFAD). Moreover, we found a not-previously reported association between ApoE epsilon 2 allele and sporadic AD and EOFAD. We included in this study two EOFAD families with the APP717 Val-->Ile mutation in the Amyloid Precursor Protein (APP) gene on chromosome 21. In any of the EOFAD families there was a significant effect of the ApoE genotype on the age of onset with the exception of one of the two mutated EOFAD families in which the 2 allele delays the age of onset.

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Ann Neurol 1995 Jul;38(1):124-7

Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer's disease.

Sorbi S, Nacmias B, Forleo P, Piacentini S, Latorraca S, Amaducci L.

Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

We found a new familial Alzheimer's disease kindred in which the disease cosegregates with the APP717Val-->Ile mutation and in which all of the three most common apolipoprotein E (ApoE) alleles are represented. We studied the relationship between ApoE genotype and the clinical expression of the disease and found that in this amyloid precursor protein-mutated family, ApoE genotype influences the age at onset of the disease. Three mutated subjects heterozygous for the epsilon 4 allele had the earliest age at onset in this family, subjects heterozygous for the epsilon 2 allele had the latest age at onset, and subjects homozygous for the epsilon 3 allele had an intermediate age at onset. In this large kindred we also found an amyloid precursor protein-mutated subject 2.4 standard deviations older than the mean age at onset without clinical signs and symptoms of the disease and carrying the epsilon 2/epsilon 3 genotype.

Alzheimer Dis Assoc Disord 1995 ;9(2):73-7

Alterations in metabolic properties in fibroblasts in Alzheimer disease.

Sorbi S, Piacentini S, Latorraca S, Piersanti P, Amaducci L.

Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

Alzheimer disease (AD) leads to alterations in several biochemical properties in cultured skin fibroblasts. Because abnormal glucose metabolism has been reported in both in vivo and in vitro studies of the brain, we examined glucose and glutamine oxidation and lactate production in cultured skin fibroblasts from nine patients with familial AD, 19 with sporadic AD, and 20 age-matched controls. The production of CO2 from glucose and glutamine was significantly lower in both groups of Alzheimer fibroblasts compared to controls after 10 min or 1, 2, and 4 h of incubation. The reduction in CO2 production was most evident after 1 h of incubation with either (U-14C)-glucose or (U-14C)-glutamine. Lactate concentration was comparable in all groups at any time of incubation. These findings suggest that processes that require mitochondrial function as glucose or glutamine oxidation are altered in AD and provide evidence that complex metabolic differences are expressed in cultured nonneuronal cells from Alzheimer patients.

Neurosci Lett 1994 Aug 15;177(1-2):100-2

ApoE allele frequencies in Italian sporadic and familial Alzheimer's disease.

Sorbi S, Nacmias B, Forleo P, Latorraca S, Gobbini I, Bracco L, Piacentini S, Amaducci L.

Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

Recent studies have provided evidence of association of apolipoprotein E (ApoE) epsilon 4 allele and late onset familial and sporadic Alzheimer's disease (AD). Epidemiological studies have established allelic variation at the ApoE locus. We have analyzed the ApoE gene polymorphism in a sample of 446 Italian subjects. Our data confirm a significant association between epsilon 4 allele and sporadic AD. The frequency of epsilon 4 allele in early onset familial AD patients was comparable to control values suggesting that epsilon 4 allele does not represent a risk factor for early onset familial AD (EOFAD). Moreover, we found a not previously reported association between ApoE epsilon 2 allele and sporadic AD and EOFAD.

Neurochem Int 1994 Jul;25(1):81-4

Molecular genetics of Alzheimer's disease in Italian families.

Sorbi S, Nacmias B, Mortilla M, Forleo P, Piacentini S, Amaducci L.

Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

We screened 11 families from different regions of Italy by direct sequencing of exon 17 of the APP gene. Two unrelated families carried the APP717 mutation segregating with the disease. These two families originate from two Italian regions which are considered genetically separate. Published studies have demonstrated the presence of the APP717 Val-->Ile mutation in kindreds of British or Japanese origin with early onset familial Alzheimer's disease. These data suggest that the APP717 mutation is not confined to islander families which may share common founders. From the molecular genetic point of view we also did linkage analysis. Several families, in fact, have not shown a linkage with chromosome 21 and the resolution of this dilemma required investigation of those pedigrees both with additional markers from chromosome 21 and with markers from other chromosomes.

Aging  1993 Dec;5(6):417-25

Molecular genetics of Alzheimer's disease.

Sorbi S.

Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

At present it is not clear whether Alzheimer's disease is a single disease, a complex syndrome, or a heterogeneous ill-defined group of disorders. In the last few years significant progress has been made in identifying and describing its different manifestations, as well as the underlying biological mechanisms. Modern molecular biology techniques have provided new insights into possible etiological mechanisms. Linkage analysis and gene sequencing studies have produced evidence of a possible locus on chromosome 21 in a small group of families with early onset familial Alzheimer's disease (FAD). It was shown that another small group of early onset FAD families develops the disease as a result of mutations in the gene coding for the beta-amyloid precursor protein, and that in a larger subgroup of early onset families the disease appears to be caused by an unidentified gene on chromosome 14. Several other early onset FAD families are clearly not linked to any of these loci, suggesting that other abnormal genes, probably on different chromosomes, might be the cause of the disease in these families. Finally, it was recently shown that the epsilon 4 allele of apolipoprotein E (ApoE) gene, which has been mapped to chromosome 19, is associated with an increased risk of developing the disease in late onset FAD families and sporadic cases. These results not only evidence that Alzheimer's disease is a genetically heterogeneous disorder, but also delineate new approaches in the study of the etiological and pathogenetic mechanisms of Alzheimer's disease.