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Abstract: The aim of this study was to evaluate the association between dementia and common vascular risk factors including blood pressure, blood lipids, homocysteine and diabetes mellitus in a population of very old people. This study is a 9-year follow-up prospective population-based study monitoring 339 non-demented subjects aged 85 years or over in the city of Vantaa, Southern Finland. During the follow-up, those individuals with diabetes mellitus at the baseline and new incident stroke had a higher probability for developing dementia. History of hypertension or higher level of education were associated with a lower probability of dementia. It seems that the contribution of vascular risk factors to the risk of dementia may be age-dependent and their role in the very old subjects may be mediated through their influence on cerebrovascular morbidity. Thus, prevention of stroke and diabetes mellitus may reduce the risk of cognitive decline in the very old. [Copyright &y& Elsevier]

In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) α-synuclein (αS) pathology is seen that displays a predictable topographic distribution. There are two staging/categorization systems, i.e. Braak’s and McKeith’s, currently in use for the assessment of αS pathology. The aim of these diagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess the probabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS). Herein, we assessed the applicability of these two staging/categorization systems and the frequency of dementia and EPS in a cohort of 226 αS-positive-subjects. These subject were selected from a large autopsy sample ( n = 1,720), irrespective of the clinical presentation, based on the detection of αS-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus, substantia nigra and basal forebrain. The frequency of αS-IR lesions in this large cohort was 14% (248 out of 1,720). If applicable, each of the 226 subjects with all required material available was assigned a neuropathological stage/category of PD/DLB and finally the neuropathological data was analyzed in relation to dementia and EPS. 83% of subjects showed a distribution pattern of αS-IR that was compatible with the current staging/categorization systems. Around 55% of subjects with widespread αS pathology (Braak’s PD stages 5–6) lacked clinical signs of dementia or EPS. Similarly, in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category and displaying only mild concomitant Alzheimer’s disease-related pathology, only 48% were demented and 54% displayed EPS. It is noteworthy that some subjects (17%) deviated from the suggested caudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitant diseases and genetic predisposition. In conclusion, our results do indeed confirm that current staging/categorization systems can readily be applied to most of the subjects with αS pathology. However, finding that around half of the subjects with abundant αS pathology remain neurologically intact is intriguing and raises the question whether we do assess the actual disease process. [ABSTRACT FROM AUTHOR]

The intracytoplasmic aggregation of α-synuclein (αS) protein is a common denominator for a group of neurodegenerative disorders currently known as synucleinopathies. It is generally assumed that the incorporation of αS protein into compact inclusions compromises the function and viability of its host cell via mechanical disruption. Herein, we report a widespread and abundant αS pathology in an elderly subject, whose medical history gave no indication of any neurodegenerative disease. We compared neuronal and glial components in this neurologically unimpaired subject with a patient with a clinical syndrome of dementia with Lewy bodies (DLB) by using a range of antigenic determinants and an in situ end-labeling technique. We detected no differences in vascular pathologies, in gliosis, or in apoptosis that would have explained the incompatible clinical end-points. With respect to the Alzheimer's disease-related changes, the only differences noted were the β-amyloid aggregates in the putamen found in the DLB patient alone. Our findings suggest that there must be some currently unidentified factors rather than αS-positive inclusions that are responsible for the neuronal dysfunction. The αS-positive inclusions may well represent detoxified reserves that cells can tolerate for years, and thus prevention of their development could actually accelerate the diseases process. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) involves increased accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles as well as neuronal loss in various regions of the neocortex. Neuroinflammation is also present, but its role in AD is not fully understood. We previously showed increased levels of pro-inflammatory cytokine interleukin-18 (IL-18) in different regions of AD brains, where it co-localized with Aβ-plaques, as well as the ability of IL-18 to increase expression of glycogen synthase kinase-3β (GSK-3β) and cyclin dependent kinase 5, involved in hyperphosphorylation of tau-protein. Elevated IL-18 has been detected in several risk conditions for AD, including obesity, type-II diabetes, and cardiovascular diseases as well as in stress.Methods: We differentiated SH-SY5Y neuroblastoma cells as neuron-like and exposed them to IL-18 for various times. We examined the protein levels of amyloid-β precursor protein (APP) and its processing products, its cleaving enzymes, involved in amyloidogenic processing of APP, and markers of apoptosis.Results: IL-18 increased protein levels of the β-site APP-cleaving enzyme BACE-1, the N-terminal fragment of presenilin-1 and slightly presenilin enhancer 2, both of which are members of the γ-secretase complex, as well as Fe65, which is a binding protein of the C-terminus of APP and one regulator for GSK-3β. IL-18 also increased APP expression and phosphorylation, which preceded increased BACE-1 levels. Further, IL-18 altered APP processing, increasing Aβ40 production in particular, which was inhibited by IL-18 binding protein. Increased levels of soluble APPβ were detected in culture medium after the IL-18 exposure. IL-18 also increased anti-apoptotic bcl-xL levels, which likely counteracted the minor increase of the pro-apoptotic caspase-3. Lactate dehydrogenase activity in culture medium was unaffected.Conclusions: The IL-18 induction of BACE-1, APP processing, and Aβ is likely to be linked to stress-associated adaptations in neurons during the course of normal functioning and development. However, in the course of wider changes in the aging brain, and particularly in AD, the effects of heightened or prolonged levels of IL-18 may contribute to the process of AD, including via increased Aβ. [ABSTRACT FROM AUTHOR]

A response by Sari Rastas and colleagues to a letter to the editor on their article "Association between Blood Pressure and Survival over 9 years in a general population aged 85 and older," in the previous issue is presented.

Abstract: A possible role of allelic variation on chromosome 19q13 in multiple sclerosis (MS) susceptibility has been suggested. We tested association of sixteen 19q13 markers with MS in 459 families. Nominally significant associations were tested in an independent set of 323 families as well as in the pooled set of 782 families. We were not able to confirm previously suggested associations with APOE, GIPR, ZNF45, ILT6 and D19S585. In the screening dataset nominally significant associations were found with D19S867 and with APOE haplotype (p =0.007 in both), but these were not replicated in the independent dataset nor in the pooled analysis of 757 families. Thus, we were not able to detect any statistically significant allelic associations. Re-sequencing based approaches may be required for elucidating the role chromosome 19q13 with MS. [Copyright &y& Elsevier]

Background/Aims: Abnormal processing of hyperphosphorylated τ (HPτ), amyloid-β (Aβ) and α-synuclein (αS) proteins is considered as causative with regard to the clinical symptoms in age-related neurodegenerative diseases. Methods: In this retrospective, postmortem study applying immunohistochemical methodology, we assessed Alzheimer’s-disease (AD)-related HPτ and Aβ pathology in 178 subjects with αS pathology. Results: These pathologies were frequently seen concomitantly, i.e. HPτ in 83% and Aβ in 62% of the αS-positive cases. Furthermore, the striatum was frequently involved, particularly in subjects with cognitive impairment (65%). The predictive value of widespread HPτ pathology, i.e. stages V–VI, with respect to cognitive impairment was high, since all 18 subjects presenting with this stage were demented. In contrast, the predictive value of widespread αS pathology, i.e. stages 5–6 according to Braak’s Parkinson disease staging, was debatable. Fifty-three percent of the subjects with widespread αS pathology and no or mild AD-related HPτ pathology were cognitively unimpaired. It is noteworthy that striatal Aβ pathology was more often seen in demented subjects independently of HPτ and/or αS status. Conclusion: The causative pathology in subjects with clinically diagnosed dementia with Lewy bodies needs to be clarified in future studies. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We present a patient with mixed connective tissue disease (MCTD) and slowly progressing demyelinating polyradiculoneuropathy (CIDP). To our knowledge, the case described is the first reported MCTD case associated with definite CIDP. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) are common manifestations of Alzheimer’ s disease (AD). Objective: To examine the prevalence and significance of NPS in very mild and mild AD patients with emphasis on their influence on the well-being of the patients and their caregivers. Methods: The participants were 240 patient-caregiver dyads who participated in a prospective, controlled rehabilitation study (ALSOVA). Three Quality of Life (QoL) instruments were used; generic 15D, disease-specific QoL-AD and Visual Analog Scale (VAS). The disease-specific QoL-AD was both selfrated and caregiver rated. Other scales used were Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), ADCS-ADL, Neuropsychiatric Inventory (NPI) and Beck Depression Inventory (BDI). Results: NPS were present in 76.5% of patients with very mild AD (CDR 0.5) and in 84.9% of patients with mild to moderate AD (CDR 1). The most frequent symptoms were apathy, depression, irritability, and agitation. The strongest predictor of self-reported QoL-AD scores was depressive symptoms whereas functional decline and presence of NPS predicted poor caregiver ratings of patients’ QoL. However, caregiver depression also influenced significantly their ratings. Conclusion: NPS are common even in the early stages of AD. NPS were significantly associated with caregiver assessment of the patient’s QoL but not with patients’ self-assessed QoL. Depression decreases QoL, but may remain unrecognized in AD patients, emphasizing the need for careful and structured assessment of NPS before deciding on the appropriate treatment. [ABSTRACT FROM AUTHOR]

Objective Amyloid-β(Aβ) aggregates are presumed to be found in the brain at an early stage of Alzheimer's disease (AD) but have seldom been assessed by brain biopsy during life in often elderly patients. Methods Between 1991 and 2006 we evaluated 468 patients with suspected normal pressure hydrocephalus with intraventricular pressure monitoring and a right frontal cortical biopsy sample immunostained for Aβ and hyperphosphorylated tau (HPτ). Adequate samples and the clinical follow-up data until death or the end of 2008, available in 433 cases, were reviewed for the clinical signs of dementia, including AD. Logistic regression analysis was used to analyze whether Aβ and/or HPτ in the biopsy samples obtained during life predicted development of cognitive impairment, in particular, AD. Results Of the 433 frontal cortical samples, 42 (10%) displayed both Aβ and HPτ, 144 (33%) Aβ only, and 247 (57%) neither Aβ nor HPτ. In a median follow-up time of 4.4 years, 94 patients (22%) developed clinical AD. The presence of both Aβ and HPτ was strongly associated (odds ratio [OR], 68.2; 95% confidence interval [CI], 22.1-210) and Aβ alone significantly associated (OR, 10.8; 95% CI, 4.9-23.8) with the clinical diagnosis of AD. Interpretation This is the largest follow-up study of patients assessed for the presence of Aβ and HPτ in frontal cortical brain biopsy samples. 1) The presence of Aβ and HPτ spoke strongly for the presence or later development of clinical AD; 2) Aβ alone was suggestive of AD; and 3) the absence of Aβ and HPτ spoke against a later clinical diagnosis of AD. Ann Neurol 2010;68:446-453 [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 112, 1386–1414. Alzheimer’s disease (AD) is a pathologically complex and aetiologically multifactorial dementing disorder affecting millions of people worldwide. The pathological brain changes are assumed to occur decades prior to the onset of clinical symptoms. The diagnosis of early AD remains problematic and is mainly based on clinical and neuropsychological findings after the onset of symptoms. Currently available drugs are able to delay the symptom progression of the disease but not to attenuate the progression of pathological brain changes. Many studies exploring AD proteomes have been conducted as the middle of 1990s as a consequence of recent advances in the development of both gel-based and gel-free proteomics approaches. It is hoped that proteomics can contribute to improving the understanding, diagnosis, and follow-up of the progression of AD. In this review, we summarise the present status of proteome alterations, with emphasis on quantitative approaches, in AD brain, CSF and blood, and their relevance to dementia research. [ABSTRACT FROM AUTHOR]

Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10−4 were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 × 10−10, OR 0.87, confidence interval 0.83–0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits. [ABSTRACT FROM AUTHOR]

Single-nucleotide polymorphisms (SNPs) in the 3′ region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS.European Journal of Human Genetics (2009) 17, 840–843; doi:10.1038/ejhg.2008.251; published online 14 January 2009 [ABSTRACT FROM AUTHOR]

Abstract: The inflammatory cytokines can initiate nerve cell degeneration and enhance the plaque production typically found in Alzheimer''s disease (AD). Interleukin-18 (IL-18) is an inflammatory cytokine, which can induce the expression of interferon-γ. This interleukin shares similarities with the IL-1 family of proteins. Like IL-1β, IL-18 is cleaved by caspase-1 (ICE) to an active secreted form. We examined the expressions of IL-18, -1β and ICE in different brain regions from AD patients that were categorized with respect to the Braak stage, and age-matched with non-demented controls. The levels of total-RNA and protein of IL-18 and ICE were increased, especially in the frontal lobe of AD patients and this change was not modified by ApoE genotype. Immunohistochemistry of AD brain samples detected IL-18 in microglia, astrocytes, and surprisingly in neurons, and it is also co-localized not only with amyloid-β plaques but also with tau. In CSF, elevated IL-18 level was detected only in men and it also correlated with CSF tau in MCI. IL-18 may thus be a potential biomarker for men. Plasma levels of IL-18 showed no correlation with the disease. In conclusion, amyloid-β may induce the synthesis of IL-18, and IL-18 kinases involved in tau phosphorylation as a part of the amyloid-associated inflammatory reaction. [Copyright &y& Elsevier]

Abstract: Loss-of-function mutations of DAP12 and TREM2 cause a recessively inherited disease PLOSL, manifesting in brain white matter. The genes of the DAP12-TREM2 signaling receptor are located on 19q13.12 and 6p21.1, to which linkage has been observed also in families affected by another immune-mediated demyelinating disease, MS. We have tested if allelic variation in DAP12 or TREM2 predisposes also to MS by monitoring carrier frequency of the Finnish PLOSL mutation in Finnish MS cases and by studying DAP12 and TREM2 in MS by linkage and association. To conclude, the DAP12-TREM2 complex unlikely has a role in genetic susceptibility of MS. [Copyright &y& Elsevier]

Abstract: Inflammatory cytokines, produced mainly by activated microglia in the brain, can enhance neuronal degeneration and the amyloid-β-plaque production involved in Alzheimer''s disease (AD). We previously demonstrated that the expression of the pro-inflammatory cytokine interleukin-18 (IL-18) colocalizes with plaques and hyperphoshorylated tau containing neurons in AD patients. Here we exposed neuron-like, differentiated SH-SY5Y neuroblastomas to IL-18 and observed that the protein levels of p35, Cdk5, GSK-3β, and Ser15-phosphorylated p53 increased during 6 h-24 h. Tau phosphorylation and expression of cyclin G1, involved in neuronal regeneration, increased at 72 h. In vivo, over-expression of IL-18 may induce hyperphosphorylation of tau and induce cell cycle activators. [Copyright &y& Elsevier]

Abstract: A three-molecular-window approach for 1H NMR spectroscopy of serum is presented to obtain specific molecular data on lipoproteins, various low-molecular-weight metabolites, and individual lipid molecules together with their degree of (poly)(un)saturation. The multiple data were analysed with self-organising maps, illustrating the strength of the approach as a holistic metabonomics framework in solely data-driven metabolic phenotyping. We studied 180 serum samples of which 30% were related to mild cognitive impairment (MCI), a neuropsychological diagnosis with severely increased risk for Alzheimer’s disease (AD). The results underline the association between MCI and the metabolic syndrome (MetS). Additionally, the low relative amount of ω-3 fatty acids appears more indicative of MCI than low serum ω-3 or polyunsaturated fatty acid concentration as such. The analyses also feature the role of elevated glycoproteins in the risk for AD, supporting the view that coexistence of inflammation and the MetS forms a high risk condition for cognitive decline. [Copyright &y& Elsevier]

Cerebrospinal fluid (CSF) biomarkers and medial temporal lobe (MTL) atrophy predict the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). We investigated the association between the CSF biomarkers and MTL atrophy and the ability of these measures to predict AD in MCI patients in the same study population. The study included 21 MCI patients of whom eight progressed to AD during the study. CSF biomarkers were measured by using ELISA method and volumes of MTL structures were assessed by magnetic resonance imaging (MRI). Abeta42 levels were lower and tau and phospho-tau levels were higher in progressive subjects. The progressive subjects had lower volumes in all MRI measures. Tau and phospho-tau correlated inversely with hippocampal volumes and left entorhinal cortex volume in the whole study group. In the stable group, tau correlated with hippocampal volumes. Phospho-tau [corrected] had a negative correlation whereas Abeta42 [corrected] exhibited a positive correlation with left hippocampal volume in the progressive group. These results indicate that both measures may reflect the ongoing neurodegenerative process in the progressive MCI patients. However, the order of the changes in the CSF biomarkers and MTL atrophy remain unclear due to a small number of studied subjects and study design. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) biomarkers and medial temporal lobe (MTL) atrophy predict the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). We investigated the association between the CSF biomarkers and MTL atrophy and the ability of these measures to predict AD in MCI patients in the same study population. The study included 21 MCI patients of whom eight progressed to AD during the study. CSF biomarkers were measured by using ELISA method and volumes of MTL structures were assessed by magnetic resonance imaging (MRI). Aβ42 levels were lower and tau and phospho-tau levels were higher in progressive subjects. The progressive subjects had lower volumes in all MRI measures. Tau and phospho-tau correlated inversely with hippocampal volumes and left entorhinal cortex volume in the whole study group. In the stable group, tau correlated with hippocampal volumes. Aβ42 had a negative correlation whereas phospho-tau exhibited a positive correlation with left hippocampal volume in the progressive group. These results indicate that both measures may reflect the ongoing neurodegenerative process in the progressive MCI patients. However, the order of the changes in the CSF biomarkers and MTL atrophy remain unclear due to a small number of studied subjects and study design. [ABSTRACT FROM AUTHOR]

To evaluate the synergistic effects of the apolipoprotein E (APOE) ε4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI).This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses. The incidence of progression to AD, cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study.Of the 1018 participants in the overall study, 464 were successfully genotyped for both APOE and butyrylcholinesterase. Of these, 68 (14.7%) carried ≥1 APOE ε4 and ≥1 BCHE-K allele. The presence of APOE ε4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression. A synergistic effect of the combined presence of APOE ε4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen. Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE ε4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE ε4 allele.In MCI, the risk of cognitive decline, hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE ε4 alleles. [ABSTRACT FROM AUTHOR]

Abstract: Background: The patients with mild cognitive impairment (MCI) have an elevated risk for Alzheimer''s disease (AD). Especially the amnestic MCI is seen as prodrome of AD. Apolipoprotein E (APOE) ɛ4 allele, abnormal CSF Aβ42, Tau and phosphorylated Tau (phospho-Tau) levels are associated with elevated risk for AD. Methods: APOE genotyping was done by PCR based method and baseline CSF Aβ42, Tau and phospho-Tau were measured by ELISA from 60 controls and 79 MCI patients. Results: Thirty-three MCI patients developed dementia during an average of 3.5 years follow-up. CSF Aβ42 was decreased and Tau and phospho-Tau were increased in the progressive MCI patients. The APOE ɛ4 allele was more frequent in the progressive MCI patients. The APOE ɛ4 allele showed a dose dependent association to the Aβ42 levels in the progressive MCI patients and to all of the markers in controls. Conclusions: Decreased CSF Aβ42 and elevated Tau or phospho-Tau together with APOE ɛ4 allele are highly predictive for the dementia in MCI patients with amnestic or executive symptoms. [Copyright &y& Elsevier]

Abstract: There is a large body of evidence highlighting the importance of oxidative stress in the pathogenesis of Alzheimer''s disease (AD). We have previously standardised a method that can be applied to study oxidative changes in individual brain proteins by using two-dimensional oxyblots (Korolainen MA, Goldsteins G, Alafuzoff I, Koistinaho J, Pirttilä T. Proteomic analysis of protein oxidation in Alzheimer''s disease brain. Electrophoresis 2002;23(19):3428–33). Here we have identified proteins that exhibited oxidative changes in AD when compared to age-matched controls and these protein changes have been further examined in relation to the neuropathological data. Indeed, several Tris–HCl soluble proteins tended to be less oxidised in AD when compared to controls. Two enzymes, mitochondrial glutamate dehydrogenase and cytosolic malate dehydrogenase, were increased in amount but showed significantly decreased degree of oxidation in AD brains when compared to controls. Furthermore, some changes related to the amounts or oxidation statuses of proteins were associated with the duration of the clinical impairment and also with the neuropathology. These results do not contradict the hypothesis of increased oxidative stress in AD but may represent co-existing compensatory changes in response to oxidative stress. [Copyright &y& Elsevier]

Abstract: Linkage analyses have identified four major MS susceptibility loci in Finns. Here we have fine mapped the region on chromosome 5p in 28 Finnish MS families. Marker D5S416 provided the highest pairwise LOD score, and multipoint and haplotype analyses restrict the critical region to about 5.3 Mb on 5p15 between markers D5S1987 and D5S416. Ascertaining for HLA type and geographical origin indicated that families with and without the HLA DR15 risk haplotype, as well as families within and outside an internal high-risk region, contributed to the linkage to 5p, implying the general significance for this locus in Finnish MS families. [Copyright &y& Elsevier]

Abstract: Chronic inflammation is known to play an important role in the heterogeneous pathogenesis of Alzheimer''s disease (AD). Activated astrocytes expressing glial fibrillary acidic protein (GFAP) are closely associated with AD pathology, such as tangles, neuritic plaques and amyloid depositions. Altogether, 46 soluble isoforms of GFAP were separated and most of them quantified by two-dimensional immunoblotting in frontal cortices of AD patients and age-matched controls. A 60% increase in the amount of more acidic isoforms of GFAP was observed in AD and these isoforms were both phosphorylated and N-glycosylated, while more basic isoforms were O-glycosylated and exhibited no quantitative differences between post-mortem AD and control brains. These data highlight the importance of exploring isoform-specific levels of proteins in pathophysiological conditions since modifications of proteins determine their activity state, localization, turnover and interaction with other molecules. Mechanisms, structures and functional consequences of modification of GFAP isoforms remain to be clarified. [Copyright &y& Elsevier]

Cyclin-dependent kinase 5 (cdk5) regulates crucial neurobiological events, and deregulation of cdk5 has been implicated in several neurodegenerative disorders. The deregulation is suggested to occur due to cleavage of the cdk5 activator protein p35 to a smaller p25 fragment by the calcium-activated protease calpain. Here we have elucidated the role of different calcium-permeable ionotropic glutamate receptors in the induction of p35 cleavage in cultured rat hippocampal neurons. The glutamate receptor agonists glutamic acid, N-methyl-d-aspartate (NMDA), kainic acid, and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) were all able to induce p35 cleavage, in a manner depending on extracellular calcium. The effect of glutamate was mediated by NMDA receptors, as it was prevented by the NMDA antagonist MK-801. Cyclothiazide (CTZ), an inhibitor of AMPA receptor desensitization, enhanced glutamate-induced p35 cleavage. In immature 6-day-old cultures the non-NMDA agonist kainic acid provoked p35 cleavage, whereas glutamate and NMDA were ineffective. The data suggest that both NMDA and non-NMDA receptors are able to induce p35 cleavage. Different factors, such as maturation state of neurons or desensitization properties of non-NMDA receptors, may determine which receptor predominantly mediates the effect of glutamate on p35 cleavage. [Copyright &y& Elsevier]

Objective: Differentiation of geriatric major depression from Alzheimer's disease is hampered by overlapping symptoms. In- creased CSF concentrations of tau protein phosphorylated at threonine 231 (p-tau[sub 231]) have been suggested as a biomarker for Alzheimer's disease. The authors asked whether p-tau[sub 231] levels improve the differential diagnosis between geriatric major depression and Alzheimer's disease. Method: Included were 34 depression subjects, 64 with probable Alzheimer's disease, 17 with possible Alzheimer's disease, and 21 healthy comparison subjects. P-tau[sub 231] concentrations were measured with an enzyme-linked immunosorbent assay. Results: P-tau[sub 231] levels were significantly higher in Alzheimer's disease than in geriatric major depression patients and healthy comparison subjects. For differentiation of probable Alzheimer's disease from major depression, p-tau[sub 231] correctly allocated 87% of subjects. When possible mild Alzheimer's disease was compared to major depression, p-tau[sub 231] correctly allocated 78% of subjects. Conclusions: CSF p-tau[sub 231] should be evaluated as a potential biological marker for differentiation of geriatric depression from Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Hyperphosphorylated tau protein is the primary component of neurofibrillary tangles observed in several neurodegenerative disorders. It has been hypothesized that in certain pathological conditions, the calcium activated protease, calpain, would cleave the cyclin-dependent kinase 5 (cdk5) activator p35 to a p25 fragment, which would lead to augmented cdk5 activity, and cdk5-mediated tau hyperphosphorylation. To test this hypothesis, we induced calpain-mediated p35 cleavage in rat hippocampal neuronal cultures and studied the relationship between p25 production, cdk5 activity, and tau phosphorylation. In glutamate-treated cells p35 was cleaved to p25 and this was associated with elevated cdk5 activity. However, tau phosphorylation was concomitantly decreased at multiple sites. The calpain inhibitor MDL28170 prevented the cleavage of p35 but had no effect on tau phosphorylation, suggesting that calpain-mediated processes, i.e., the cleavage of p35 to p25 and cdk5 activation, do not contribute to tau phosphorylation in these conditions. Treatment of the neuronal cultures with N-methyl-d-aspartic acid or with calcium ionophores resulted in an outcome highly similar to that of glutamate. We conclude that, in neuronal cells, the cleavage of p35 to p25 is associated with increased activity of cdk5 but not with tau hyperphosphorylation. [Copyright &y& Elsevier]

Cyclin-dependent kinase 5 (cdk5) is involved in the development of the nervous system and neuronal process outgrowth, and it regulates several intracellular processes including cytoskeletal dynamics. Dysregulation of cdk5 has been implicated in many disorders of the nervous system. The activity of the kinase is regulated by binding of cdk5 activators (p35, p39, p67). We examined the phosphorylation of p35, and the role of phosphorylation in regulating the proteolysis of the p35 protein. By detecting changes in electrophoretic mobility, we observed that a significant proportion of p35 is phosphorylated in rat brain tissue. In cultured neurons, the phosphorylation was prevented by roscovitine, an inhibitor of cdk5 and some other cdks. The phosphatase inhibitor okadaic acid induced p35 degradation in neuronal cultures which was sensitive to the proteasome inhibitor lactacystin. These latter results agree with some previous studies showing that phosphorylation regulates proteasomal degradation of p35. Treatment of brain homogenate with okadaic acid in the presence of ATP led to accumulation of p35 phosphorylated also by a kinase that was not inhibited by roscovitine. This implies that the effect of okadaic acid on p35 degradation could also be contributed by a non-cdk kinase. The calpain protease has been shown to cleave p35. Our results suggest that this process may also be modulated by p35 phosphorylation under some conditions. We conclude that p35 phosphorylation influences the proteasome-mediated degradation of p35 and calpain-mediated cleavage of p35 to p25. [Copyright &y& Elsevier]

Abstract: Recently, the P86L alteration in CALHM1 (calcium homeostasis modulator-1) was reported to be associated with Alzheimer''s disease (AD). Moreover, the risk allele increased amyloid-β (Aβ) levels in conditioned media from cultured cells. Therefore, we hypothesized that CALHM1 P86L may modulate Aβ or tau levels in cerebrospinal fluid (CSF). Nearly 200 individuals with AD or other cognitive disorders were included for CSF analysis and CALHM1 genotyping. No significant differences in CSF levels of Aβ42, tau or phospho-tau were found across the various CALHM1 genotypes. In conclusion, we found no evidence that CALHM1 P86L is associated with altered CSF levels of the investigated AD biomarkers. [Copyright &y& Elsevier]

Abstract: The tenomodulin gene (TNMD, locus Xq-22) encodes an angiogenesis inhibitor. It is an interesting candidate gene for Alzheimer''s disease (AD), since it is expressed in brain, alterations in angiogenesis have been linked to AD and in our previous studies we have observed associations between TNMD and phenotypes, which are related to increased risk of AD. The common sequence variation in the TNMD was not associated with prevalence of AD among 526 cases and 672 controls. However, a significant interaction (p =0.002) between rs5966709 and the APOE ε4-allele status was observed in women. Among the ε4-allele carriers, the women with rs5966709-TT genotype had smaller risk for having AD than those with other genotypes (odds ratio 0.47, p =0.019, false discovery rate 10.4%). According to these results the sequence variation of TNMD is not associated with AD, but might modify the effect of APOE ε4-allele in women. [Copyright &y& Elsevier]