Apolipoprotein(a) [apo(a)] is a highly polymorphic glycoprotein which has been suggested to play a role in Alzheimer's disease (AD). Plasma lipoprotein(a) [Lp(a)] levels and the differential expression of apo(a) isoforms were analyzed in 73 sporadic AD patients compared with 73 age- and gender-matched healthy controls. The distribution of apo(a) isoforms and Lp(a) concentrations were similar in the two groups. However, we observed that AD patients with no apo(a) isoform from immunoblots (subjects with the ‘null phenotype’) had a mean age at onset of 76.8±8.8 versus 66.9±9.6 years of those who expressed at least one apo(a) band (P=0.010). Multivariate analysis showed that this effect was independent of apolipoproteinE ϵ4 allele. We conclude that the expression of at least one apo(a) isoform may interact with other pathogenic mechanisms involved in controlling the age at onset of AD.

Lipoprotein(a) [Lp(a)] level is a newly established vascular risk factor which has been suggested to play a role in dementia. However, the majority of Lp(a) cell-to-cell interactions are mediated by its specific apolipoprotein(a) [apo(a)] moiety. This suggests that the size polymorphism of apo(a) may be of importance in conveying the Lp(a)-related risk. Specifically, we postulated that variation in apo(a) isoform size may lead to increased risk of vascular dementia (VaD), Alzheimer’s disease (AD), stroke, or all three of them. Under a case-control design we compared Lp(a) plasma levels and the distribution of apo(a) phenotypes in groups of subjects consisting of 50 VaD patients, 162 sporadic AD patients, 95 non-demented stroke patients (NDS), and 105 normal controls. The prevalence of small-sized apo(a) isoforms in the VaD group was significantly higher than that in the stroke and normal control groups, with an odds ratio of 5.29 (95% CI 2.24–12.49, p = 0.0001) for the development of VaD for individuals with at least one apo(a) isoform of low molecular weight (LMW). Furthermore, the possession of at least one small-sized apo(a) isoform significantly increased the risk of AD to 1.92 (95% CI 1.02–3.61, p = 0.0434). Our results demonstrate that possession of at least one LMW apo(a) isoform is significantly associated with dementia and specifically offer new evidence of a strong association between the lipoprotein system and post-stroke dementia.

Caveolin-1 (Cav-1) is a transmembrane protein which clusters proteins and lipids at the cell membrane into a subclass of lipid rafts named caveolae. To increase our understanding about putative functions of Cav-1 in neuronal cells, we used mouse brain extracts and a novel technology coupling surface plasmon resonance to mass spectrometry to find binding partners to Cav-1. An interaction between Cav-1 and alpha-synclein was found and confirmed in reciprocal pulldown experiments. Genetic overexpression of alpha-synclein in mouse neuroblastoma Neuro2A cells (N2A) expectedly decreased cell survival, but also significantly increased the levels of Cav-1. Furthermore, si-RNA-mediated knockdown of Cav-1 counteracted cell death induced by overexpression of alpha-synuclein. We also used an inhibitor of proteasome (MG132) to induce cell death in a Parkinson’s disease context. Cav-1 knockdown had no effect on cell death induced by MG132. Conversely, treating the cells with mevastatin, an inhibitor of cholesterol synthesis, inhibits cell death induced by MG132, but not by alpha synuclein overexpression. It can be concluded that Cav-1 may play a functional role in neuronal cells by virtue of its physical interaction with alpha-synuclein and regulate alpha synuclein-mediated actions on cell death, processes known to be involved in synucleinopathies including Parkinson’s disease.

Brain deposition of the amyloid-β protein (Aβ) is a frequent complication of Down’s syndrome (DS) patients. Aβ peptide is generated by endoproteolytic processing of Aβ precursor protein by γ and β secretases. Recently a transmembrane aspartyl protease, BACE, has been identified as the β-secretase, and its homologous BACE-2 has also been described. BACE-2 gene resides on chromosome 21 in the obligate DS region. It cleaves Aβ precursor protein at its β site and more efficiently at a different site within Aβ. In the present study we characterized the BACE-2 gene and protein expression in the DS patients and healthy control. We analyzed, by using a nonradioactive ribonuclease protection assay, the levels of BACE-2 mRNA expression in primary skin fibroblasts. The analysis revealed a 2.6-fold increase in BACE-2 mRNA levels in the DS group compared to the levels observed in the control group. Western blot analysis revealed no difference between DS and control in BACE-2 protein levels in the intracellular compartment. In the medium conditioned by fibroblast, we revealed an evident secretion of BACE-2 protein, represented by two different molecular weights, remarkably increased in DS fibroblasts. BACE-2 overexpression was also confirmed in the DS fetal brains and human neural embryonic DS stem cells in which conditioned media BACE-2 was secreted. These data highlight the importance of the extracellular compartment where BACE-2 overexpression could play a role in plaque formation in DS patients.

CST3 is the coding gene for cystatin C (CysC). CST3 B/B homozygosity is associated with an increased risk of developing Alzheimer disease. We performed CysC analysis on human primary skin fibroblasts obtained from donors carrying A/A, A/B, and B/B CST3. Pulse-chase experiments demonstrated that the release of the B variant of CysC has a different temporal pattern compared to that of the A one. Fibroblasts B/B homozygous displayed a reduced secretion of CysC due to a less efficient cleavage of the signal peptide, as suggested by high-resolution Western blot analysis and by in vitro assay. In the brain, the reduced level of CysC may represent the molecular factor responsible for the increased risk of Alzheimer disease.

We describe an Italian pedigree with hereditary dementia associated with a novel T122R mutation in the presenilin-2 gene (PSEN2). The clinical history, symptom presentation, and structural neuroimaging were consistent with an atypical form of dementia. Disease expression varied within family members. One in a pair of mutated monozygotic twins had evident signs of disease, whereas the other did not, even if her functional neuroimaging investigations, cerebrospinal fluid levels of Abeta1-42, and Tau protein were able to provide markers for future disease development. These observations suggest the importance of still unknown biological and perhaps environmental factors in the disease determination.

Frontotemporal dementia (FTD) is a clinical entity grouping different diagnostic conditions. FTD can occur in a sporadic form; however in 30–50% of cases a familial form of FTD has been observed. Mutations in the TAU gene were associated to familial FTD linked to chromosome 17. Our aim was to investigated the proportion of FTD cases attributable to TAU gene mutations in an Italian clinical series. We analyzed 38 patients with FTD; of these, 13 had a positive family history of FTD. All TAU gene exons and flanking intronic regions were sequenced. In our familial FTD sample the estimation of TAU gene mutations accounted for a relative low prevalence (7.6%); based on our results we could argue the existence of other mutations in regulatory regions in the TAU gene or, on the other hand, other genes might be responsible for the most cases of familial FTD.

Apolipoprotein(a) [apo(a)] is a genetically polymorphic glycoprotein that has several similarities to apolipoprotein E. However, its role as a risk factor for frontotemporal dementia (FTD) remains to be elucidated. We therefore investigated the effect of an apo(a) polymorphism on the incidence of FTD in a sample of Caucasian Italian patients. From the entire group of FTD patients (n=54), 55.6% of the subjects had at least one apo(a) low molecular weight (MW) isoform, compared to 29.9% of non-demented controls (n=77). The difference between the two groups was statistically significant (odds ratio 2.93, 95% confidence interval 1.42–6.06, P=0.003). The FTD group was further divided into sporadic (n=26) and familial (n=28) cases. Even after such dichotomization, both sporadic and familial FTD patients showed a significantly higher prevalence of low MW apo(a) isoforms than the cognitively healthy controls (P=0.011 and P=0.025, respectively). Our data suggest a role of apo(a) phenotypes of low MW in mediating susceptibility to FTD.