Professor in Geriatric Medicine, neurogeriatritian, Karolinska Institutet , Karolinska University Hospital and University in Osloexpertise: geriatric, neurology, neuropathology, neuroanatomy and imaging, drug development, preclinical sciences and translationa medicine
Autosomal-dominant Alzheimer’s disease (ADAD) may be associated with atypical amyloid beta deposi... more Autosomal-dominant Alzheimer’s disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using 11C-Pittsburgh compound B (PiB) tracer has shown differences in binding between brains from ADAD and sporadic Alzheimer’s disease (sAD) patients. To gain further insight into the various pathological characteristics of these genetic variants, we performed large frozen hemisphere autoradiography and brain homogenate binding assays with 3H-PiB, 3H-MK6240-3H-THK5117, and 3H-deprenyl for detection of amyloid fibrils, tau depositions, and activated astrocytes, respectively, in two AβPParc mutation carriers, one PSEN1ΔE9 mutation carrier, and three sAD cases. The results were compared with Abeta 40, Abeta 42, AT8, and GFAP immunostaining, respectively, as well as with Congo red and Bielschowsky. PiB showed a very low binding in AβPParc. A high binding was observed in PSEN1ΔE9 and in sAD tissues but with different binding patterns. Comparable 3H-TH...
Synaptic dysfunction is an early pathogenic event in Alzheimer disease (AD) that contributes to n... more Synaptic dysfunction is an early pathogenic event in Alzheimer disease (AD) that contributes to network disturbances and cognitive decline. Some synapses are more vulnerable than others, including the synapses of the perforant path, which provides the main excitatory input to the hippocampus. To elucidate the molecular mechanisms underlying the dysfunction of these synapses, we performed an explorative proteomic study of the dentate terminal zone of the perforant path. The outer two-thirds of the molecular layer of the dentate gyrus, where the perforant path synapses are located, was microdissected from five subjects with AD and five controls. The microdissected tissues were dissolved and digested by trypsin. Peptides from each sample were labeled with different isobaric tags, pooled together and pre-fractionated into 72 fractions by high-resolution isoelectric focusing. Each fraction was then analyzed by liquid chromatography-mass spectrometry. We quantified the relative expression...
Alzheimer’s disease (AD) is characterized by impaired protein homeostasis leading to amyloid-beta... more Alzheimer’s disease (AD) is characterized by impaired protein homeostasis leading to amyloid-beta (Aβ) amyloidosis. Here, we show that autophagy is similarly inhibited in AD brains and App knock-in AD mouse models. To determine how pathologies translate to cerebrospinal fluid (CSF), label-free mass spectrometry of mouse CSF was used. This identified autophagy-related extracellular matrix (ECM) protein decorin as significantly and similarly increased in App knock-in mice and cognitively normal human subjects with abnormal CSF-amyloid. Notably, a switch from negative to positive correlation of CSF-decorin and CSF-amyloid occurs in cognitively normal subjects when CSF-amyloid becomes abnormal, indicating an early change in CSF-decorin induced by Aβ amyloidosis. In App knock-in mice increased CSF-decorin correlated with accentuated decorin expression in choroid plexus and decreased interneuronal decorin. Furthermore, decorin activates neuronal autophagy-lysosomal system by enhancing lys...
Aims: To examine the degree of agreement between self- and informant ratings of personality in re... more Aims: To examine the degree of agreement between self- and informant ratings of personality in relation to cognitive function in patients with mild cognitive impairment (MCI), subjective cognitive impairment (SCI) and healthy controls (HC). Methods: Thirty-two patients and informants with MCI, 23 with SCI and 22 HC completed the Swedish universities Scales of Personality (SSP). Correlations and incongruence between self- and informant ratings were calculated. The Mini Mental State Examination (MMSE) was used to assess cognitive function. Results: The correlations between self- and informant ratings were fair-to-moderate on a majority of SSP scales and significant in 44%. The incongruence between patients and informants was significantly larger in MCI than in HC across SSP scales. There was a significant negative correlation between the incongruence index and the MMSE for all subjects. Conclusions: Self-informant agreement on ratings of patients’ personality was reasonable. Incongruence between patients and their informants was associated with MCI but not SCI or HC. Disagreement between patients and informants indicates cognitive impairment.
A polymorphism consisting of a deletion near the 5Ј splice site of exon 18 on the α2-macroglobuli... more A polymorphism consisting of a deletion near the 5Ј splice site of exon 18 on the α2-macroglobulin (A2M) gene (A2M-2) has been suggested to be associated with Alzheimer's disease (AD) in family-based studies. We studied the A2M-2 allele together with the ApoE alleles in a large series on patients with AD (n ϭ 449) and age-matched controls (n ϭ 349). Neuropathologically confirmed diagnoses were available in 199 cases (94 AD and 107 control cases). We found no increase in A2M-2 genotype or allele frequencies in AD (27.5% and 14.6%) versus controls (26.4% and 14.9%). In contrast, a marked increase (p Ͻ 0.0001) in ApoE ε4 genotype or allele frequencies was found in AD (66.6% and 41.2%) as compared with controls (29.8% and 16.5%), suggesting sufficient statistical power in our sample. No relation was found between the A2M-2 and the ApoE ε4 allele. No change in A2M exon 17-18 mRNA size or sequence or A2M protein size was found in cases carrying the A2M-2 deletion, suggesting that there is no biological consequences of the A2M intronic deletion. No change in A2M protein level in cerebrospinal fluid was found in AD, suggesting that the A2M-2 allele does not effect the A2M protein expression in the brain. The lack of an association between the A2M-2 allele and AD in the present study, and the lack of abnormalities in the A2M mRNA or protein suggest that the A2M-2 allele is not associated with AD.
Over the past decade, it has become apparent that the neuroprotective action of oestrogens may re... more Over the past decade, it has become apparent that the neuroprotective action of oestrogens may result from the oestrogen receptor (ER)-dependent and-independent mechanisms (1, 2). The ERdependent mechanisms may be exerted via genomic way (i.e. through the activation of intracellular ERa and ERb and oestrogen target genes) (3, 4). In addition, the nongenomic ER-dependent mechanisms of oestrogens in target cells and tissues have been described (5, 6). These steroids may interact with the plasma membrane-located ER-like proteins that can activate the G-protein mediated downstream signalling (e.g. cAMP and protein kinase C
Journal of Cellular and Molecular Medicine, Oct 23, 2008
The hippocampus of aged rats shows marked age-related morphological changes that could cause memo... more The hippocampus of aged rats shows marked age-related morphological changes that could cause memory deficits. Experimental evidence has established that environmental enrichment attenuates memory deficits in aged rats. We therefore studied whether environmental enrichment produces morphological changes on the dentate granule cells of aged rats. Fifteen male Sprague-Dawley rats, 24 months of age, were randomly distributed in two groups that were housed under standard (n ϭ 7) or enriched (n ϭ 8) environmental conditions for 26 days. Quantitative data of dendritic morphology from dentate gyrus granule cells were obtained on Golgi-Cox stained sections. Environmental enrichment significantly increased the complexity and size of dendritic tree (total number of segments increased by 61% and length by 116%), and spine density (88% increase). There were large interindividual differences within the enriched group, indicating differential individual responses to environmental stimulation. Previous studies in young animals have shown changes produced by environmental enrichment in the morphology of dentate gyrus granule cells. The results of the present study show that environmental enrichment can also produce changes in dentate granule cell morphology in the senescent brain. In conclusion, the hippocampus retains its neuroplastic capacity during aging, and enriched environmental housing conditions can attenuate age-related dendritic regression and synaptic loss, thus preserving memory functions.
The antioxidant potency of three natural polyphenols, resveratrol, curcumin, and genistein, was c... more The antioxidant potency of three natural polyphenols, resveratrol, curcumin, and genistein, was compared by using the two human models: oxymodified with H(2)O(2) and homocysteine (Hcy) G proteins in the postmortem frontal cortex (FC) membranes of age-matched control and Alzheimer's disease (AD) subjects; and Cu(2+)-induced oxidation of plasma low-density lipoproteins (LDL). In Co, 3-10 microM polyphenols dose-dependently depressed the G protein 25% stimulation induced by 10 microM H(2)O(2) or 500 microM Hcy. Resveratrol revealed significantly higher antioxidativity than curcumin or genistein. In AD, the antioxidativity of polyphenols showed no significant differences. Polyphenols (1 microM) significantly increased the LDL oxidation lag time (oxyresistance) as compared with control, the effect of resveratrol being most potent. Due to the dual antioxidant mechanism, the investigated polyphenols, particularly resveratrol, should have preferences for the preventive-therapeutic use in age-related oxidative stress-based pathologies.
Linkage studies have implicated a broad region on chromosome 10q in Alzheimer's disease (AD). A r... more Linkage studies have implicated a broad region on chromosome 10q in Alzheimer's disease (AD). A recent genetic association study has provided evidence that polymorphism in the gene encoding alpha-3 catenin (CTNNA3, referred to previously as VR22 and also known as alpha-T catenin) may underlie linkage signals. Here, to investigate this finding, markers that previously exhibited maximum evidence of association have been tested in Swedish and Scottish AD case-control samples. Across models of disease risk and in relation to multiple quantitative indices of AD pathology (CSF Ab42 and tau levels, age-at-onset, MMSE scores, and measures of senile plaque density) no evidence was found supporting a role for these particular variants in AD. More detailed studies of regional linkage disequilibrium structure around CTNNA3 will likely be required to determine whether sequence variation in this region impacts AD.
Journal of Cellular and Molecular Medicine, Dec 1, 2009
The blood-brain barrier (BBB) is a tightly controlled semi-permeable barrier which prevents the p... more The blood-brain barrier (BBB) is a tightly controlled semi-permeable barrier which prevents the paracellular passage for macro-molecules and cells from the blood stream into the brain [1]. It consists primarily of capillary endothelial cells packed together by tight junctions (TJs), together with the adjoining astrocyte endfeet and pericytes. TJs are specialized membrane domains at the most apical region of epithelial and endothelial cells, involved in both prevention of solute and water leakage (barrier function) and maintenance of cellular polarity (fence function) [2]. In the brain of vertebrates there are two types of cells which are known to bear TJs or TJs-like structures: vascular endothelial cells and oligodendrocytes [3]. TJs networks are formed by integral membrane proteins, such as junctional associated membrane protein 1 [4],
Objectives: The purpose of the present study was to investigate patterns of personality in patien... more Objectives: The purpose of the present study was to investigate patterns of personality in patients with subjective cognitive impairment (SCI) and mild cognitive impairment (MCI), compared to healthy controls. Methods: We assessed24 patients with SCI, 35 patients with MCI and 26 healthy controls with the self-report questionnaire Swedish Universities Scales of Personality measuring aspects of neuroticism/anxiety proneness, extraversion, and aggression-hostility. Results: Patients with SCI and MCI showed significantly more Somatic Trait Anxiety, Psychic Trait Anxiety and Stress Susceptibility than healthy controls. Moreover, there was a significant increase in Detachment in patients with MCI and a significant decrease in Adventure Seeking in patients with SCI, relative to healthy controls. Conclusions: Patients with SCI and MCI presented specific patterns of personality alterations with higher scores in traits related to anxiety proneness and aggression-hostility and lower in traits of extraversion. In most subscales differences followed a sequential pattern with gradually increasing scores from healthy controls, to patients with SCI and further to MCI. The groups differed in amount and type of symptoms, suggesting that patterns of personality may be related to degree of cognitive impairment.
The presynaptically located γ-aminobutyric acid (GABA) transporter (GAT-1) was studied in a group... more The presynaptically located γ-aminobutyric acid (GABA) transporter (GAT-1) was studied in a group of patients with Alzheimer's disease (AD) and in a control group using the GAT-1 selective radioligand [ 3 H]tiagabine. Post mortem brain tissue from frontal cortex, temporal cortex, and caudate nucleus from 18 AD patients and 23 age-matched controls were studied. The binding was saturable (Kd 26 nM) and region specific. There were no significant differences between the groups with respect to the binding capacity (Bmax) and binding affinity (Kd). The unaltered [ 3 H]tiagabine binding to GAT-1 protein indicates that intrinsic GABA neurons are spared in Alzheimer's disease.
Most genetic sequence variants that contribute to variability in complex human traits will have s... more Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004-April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) beta-amyloid (Abeta) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.
American Journal of Medical Genetics - Neuropsychiatric Genetics, Dec 28, 2007
Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several epidemiological... more Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several epidemiological and biochemical features. The present study aimed to assess the possible influence of the AMD-associated complement factor H (CFH) Y402H (1277T > C) polymorphism on the risk of AD. Caucasian subjects (n ¼ 800) meeting the criteria for probable (n ¼ 717) or definite (n ¼ 83) AD and Caucasian non-demented controls (n ¼ 1265) were included in this multi-center casecontrol study, in which genotype and allele frequencies of the CFH 1277T > C polymorphism were determined and related to diagnosis, APOE genotype, Mini-Mental State Examination score (MMSE) and the cerebrospinal fluid (CSF) biomarkers total-tau (T-tau), phospho-tau 181 (P-tau 181), and b-amyloid 1-42 (Ab 1-42). The AMDassociated CFH genotypes (1277CC and 1277TC) were overrepresented in subjects with AD as compared to control individuals (P ¼ 0.029). Positive C carrier status was associated with an odds ratio (OR) for AD of 1.24 (95% confidence interval [CI] 1.02-1.50). When APOE e4 carrier status was included in the regression model, this association was even stronger (OR 1.34, 95% CI: 1.08-1.65, P ¼ 0.007). Subgroup analysis showed that the association between CFH C allele positivity and AD was only evident for individuals carrying the APOE e4 allele. Positive C carrier status was also associated with lower levels of CSF Ab 1-42 selectively in the control group in an APOE e4-independent manner (P ¼ 0.003). In conclusion, the CFH 1277T > C polymorphism seems to influence the risk of AD and there appears to be an interaction between CFH 1277C and APOE e4 alleles. The CFH 1277C allele may predispose patients for co-morbidity in AD and AMD.
The -amyloid peptide (A) is a major component of Alzheimer disease (AD)-associated senile plaqu... more The -amyloid peptide (A) is a major component of Alzheimer disease (AD)-associated senile plaques and is generated by sequential cleavage of the -amyloid precursor protein (APP) by -secretase (BACE1) and ␥-secretase. BACE1 cleaves APP at the N terminus of the A domain, generating a membrane-bound C-terminal fragment (CTF-) that can be subsequently cleaved by ␥-secretase within the transmembrane domain to release A. Because BACE1 initiates A generation, it represents a potential target molecule to interfere with A production in therapeutic strategies for AD. BACE1 interacts with Golgi-localized, ␥-ear-containing, ADP ribosylation factor-binding (GGA) proteins that are involved in the subcellular trafficking of BACE1. Here, we show that GGA1 is preferentially expressed in neurons of the human brain. GGA1 was also detected in activated microglia surrounding amyloid plaques in AD brains. Functional analyses with cultured cells demonstrate that GGA1 is implicated in the proteolytic processing of APP. Overexpression of GGA1 or a dominant-negative variant reduced cleavage of APP by BACE1 as indicated by a decrease in CTF- generation. Importantly, overexpression of GGA1 reduced, whereas RNAi-mediated suppression of GGA1 increased the secretion of A. The modulation of APP processing by GGA1 is independent of a direct interaction of both proteins. Because total cellular activity of BACE1 was not affected by GGA1 expression, our data indicate that changes in the subcellular trafficking of BACE1 or other GGA1-dependent proteins contribute to changes in APP processing and A generation. Thus, GGA proteins might be involved in the pathogenesis of AD.
The endocytic pathway is important in amyloid precursor protein (APP) processing and β‐amyloid fo... more The endocytic pathway is important in amyloid precursor protein (APP) processing and β‐amyloid formation. Our studies have shown that endocytic pathway activation is a prominent and early feature of neurons in vulnerable regions of the brain in sporadic Alzheimer's disease. We report that endocytic pathway abnormalities are present not only in neurons, but in cerebral endothelia in Alzheimer's disease caused by certain APP mutations. The presence or absence of endocytic abnormalities distinguish subtypes of familial Alzheimer's disease linked to APP mutations from presenilin mutations, supporting the notion that different cellular pathways are involved in the altered processing of APP leading to increased β‐amyloid generation in certain of these different Alzheimer's disease subtypes.
Autosomal-dominant Alzheimer’s disease (ADAD) may be associated with atypical amyloid beta deposi... more Autosomal-dominant Alzheimer’s disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using 11C-Pittsburgh compound B (PiB) tracer has shown differences in binding between brains from ADAD and sporadic Alzheimer’s disease (sAD) patients. To gain further insight into the various pathological characteristics of these genetic variants, we performed large frozen hemisphere autoradiography and brain homogenate binding assays with 3H-PiB, 3H-MK6240-3H-THK5117, and 3H-deprenyl for detection of amyloid fibrils, tau depositions, and activated astrocytes, respectively, in two AβPParc mutation carriers, one PSEN1ΔE9 mutation carrier, and three sAD cases. The results were compared with Abeta 40, Abeta 42, AT8, and GFAP immunostaining, respectively, as well as with Congo red and Bielschowsky. PiB showed a very low binding in AβPParc. A high binding was observed in PSEN1ΔE9 and in sAD tissues but with different binding patterns. Comparable 3H-TH...
Synaptic dysfunction is an early pathogenic event in Alzheimer disease (AD) that contributes to n... more Synaptic dysfunction is an early pathogenic event in Alzheimer disease (AD) that contributes to network disturbances and cognitive decline. Some synapses are more vulnerable than others, including the synapses of the perforant path, which provides the main excitatory input to the hippocampus. To elucidate the molecular mechanisms underlying the dysfunction of these synapses, we performed an explorative proteomic study of the dentate terminal zone of the perforant path. The outer two-thirds of the molecular layer of the dentate gyrus, where the perforant path synapses are located, was microdissected from five subjects with AD and five controls. The microdissected tissues were dissolved and digested by trypsin. Peptides from each sample were labeled with different isobaric tags, pooled together and pre-fractionated into 72 fractions by high-resolution isoelectric focusing. Each fraction was then analyzed by liquid chromatography-mass spectrometry. We quantified the relative expression...
Alzheimer’s disease (AD) is characterized by impaired protein homeostasis leading to amyloid-beta... more Alzheimer’s disease (AD) is characterized by impaired protein homeostasis leading to amyloid-beta (Aβ) amyloidosis. Here, we show that autophagy is similarly inhibited in AD brains and App knock-in AD mouse models. To determine how pathologies translate to cerebrospinal fluid (CSF), label-free mass spectrometry of mouse CSF was used. This identified autophagy-related extracellular matrix (ECM) protein decorin as significantly and similarly increased in App knock-in mice and cognitively normal human subjects with abnormal CSF-amyloid. Notably, a switch from negative to positive correlation of CSF-decorin and CSF-amyloid occurs in cognitively normal subjects when CSF-amyloid becomes abnormal, indicating an early change in CSF-decorin induced by Aβ amyloidosis. In App knock-in mice increased CSF-decorin correlated with accentuated decorin expression in choroid plexus and decreased interneuronal decorin. Furthermore, decorin activates neuronal autophagy-lysosomal system by enhancing lys...
Aims: To examine the degree of agreement between self- and informant ratings of personality in re... more Aims: To examine the degree of agreement between self- and informant ratings of personality in relation to cognitive function in patients with mild cognitive impairment (MCI), subjective cognitive impairment (SCI) and healthy controls (HC). Methods: Thirty-two patients and informants with MCI, 23 with SCI and 22 HC completed the Swedish universities Scales of Personality (SSP). Correlations and incongruence between self- and informant ratings were calculated. The Mini Mental State Examination (MMSE) was used to assess cognitive function. Results: The correlations between self- and informant ratings were fair-to-moderate on a majority of SSP scales and significant in 44%. The incongruence between patients and informants was significantly larger in MCI than in HC across SSP scales. There was a significant negative correlation between the incongruence index and the MMSE for all subjects. Conclusions: Self-informant agreement on ratings of patients’ personality was reasonable. Incongruence between patients and their informants was associated with MCI but not SCI or HC. Disagreement between patients and informants indicates cognitive impairment.
A polymorphism consisting of a deletion near the 5Ј splice site of exon 18 on the α2-macroglobuli... more A polymorphism consisting of a deletion near the 5Ј splice site of exon 18 on the α2-macroglobulin (A2M) gene (A2M-2) has been suggested to be associated with Alzheimer's disease (AD) in family-based studies. We studied the A2M-2 allele together with the ApoE alleles in a large series on patients with AD (n ϭ 449) and age-matched controls (n ϭ 349). Neuropathologically confirmed diagnoses were available in 199 cases (94 AD and 107 control cases). We found no increase in A2M-2 genotype or allele frequencies in AD (27.5% and 14.6%) versus controls (26.4% and 14.9%). In contrast, a marked increase (p Ͻ 0.0001) in ApoE ε4 genotype or allele frequencies was found in AD (66.6% and 41.2%) as compared with controls (29.8% and 16.5%), suggesting sufficient statistical power in our sample. No relation was found between the A2M-2 and the ApoE ε4 allele. No change in A2M exon 17-18 mRNA size or sequence or A2M protein size was found in cases carrying the A2M-2 deletion, suggesting that there is no biological consequences of the A2M intronic deletion. No change in A2M protein level in cerebrospinal fluid was found in AD, suggesting that the A2M-2 allele does not effect the A2M protein expression in the brain. The lack of an association between the A2M-2 allele and AD in the present study, and the lack of abnormalities in the A2M mRNA or protein suggest that the A2M-2 allele is not associated with AD.
Over the past decade, it has become apparent that the neuroprotective action of oestrogens may re... more Over the past decade, it has become apparent that the neuroprotective action of oestrogens may result from the oestrogen receptor (ER)-dependent and-independent mechanisms (1, 2). The ERdependent mechanisms may be exerted via genomic way (i.e. through the activation of intracellular ERa and ERb and oestrogen target genes) (3, 4). In addition, the nongenomic ER-dependent mechanisms of oestrogens in target cells and tissues have been described (5, 6). These steroids may interact with the plasma membrane-located ER-like proteins that can activate the G-protein mediated downstream signalling (e.g. cAMP and protein kinase C
Journal of Cellular and Molecular Medicine, Oct 23, 2008
The hippocampus of aged rats shows marked age-related morphological changes that could cause memo... more The hippocampus of aged rats shows marked age-related morphological changes that could cause memory deficits. Experimental evidence has established that environmental enrichment attenuates memory deficits in aged rats. We therefore studied whether environmental enrichment produces morphological changes on the dentate granule cells of aged rats. Fifteen male Sprague-Dawley rats, 24 months of age, were randomly distributed in two groups that were housed under standard (n ϭ 7) or enriched (n ϭ 8) environmental conditions for 26 days. Quantitative data of dendritic morphology from dentate gyrus granule cells were obtained on Golgi-Cox stained sections. Environmental enrichment significantly increased the complexity and size of dendritic tree (total number of segments increased by 61% and length by 116%), and spine density (88% increase). There were large interindividual differences within the enriched group, indicating differential individual responses to environmental stimulation. Previous studies in young animals have shown changes produced by environmental enrichment in the morphology of dentate gyrus granule cells. The results of the present study show that environmental enrichment can also produce changes in dentate granule cell morphology in the senescent brain. In conclusion, the hippocampus retains its neuroplastic capacity during aging, and enriched environmental housing conditions can attenuate age-related dendritic regression and synaptic loss, thus preserving memory functions.
The antioxidant potency of three natural polyphenols, resveratrol, curcumin, and genistein, was c... more The antioxidant potency of three natural polyphenols, resveratrol, curcumin, and genistein, was compared by using the two human models: oxymodified with H(2)O(2) and homocysteine (Hcy) G proteins in the postmortem frontal cortex (FC) membranes of age-matched control and Alzheimer's disease (AD) subjects; and Cu(2+)-induced oxidation of plasma low-density lipoproteins (LDL). In Co, 3-10 microM polyphenols dose-dependently depressed the G protein 25% stimulation induced by 10 microM H(2)O(2) or 500 microM Hcy. Resveratrol revealed significantly higher antioxidativity than curcumin or genistein. In AD, the antioxidativity of polyphenols showed no significant differences. Polyphenols (1 microM) significantly increased the LDL oxidation lag time (oxyresistance) as compared with control, the effect of resveratrol being most potent. Due to the dual antioxidant mechanism, the investigated polyphenols, particularly resveratrol, should have preferences for the preventive-therapeutic use in age-related oxidative stress-based pathologies.
Linkage studies have implicated a broad region on chromosome 10q in Alzheimer's disease (AD). A r... more Linkage studies have implicated a broad region on chromosome 10q in Alzheimer's disease (AD). A recent genetic association study has provided evidence that polymorphism in the gene encoding alpha-3 catenin (CTNNA3, referred to previously as VR22 and also known as alpha-T catenin) may underlie linkage signals. Here, to investigate this finding, markers that previously exhibited maximum evidence of association have been tested in Swedish and Scottish AD case-control samples. Across models of disease risk and in relation to multiple quantitative indices of AD pathology (CSF Ab42 and tau levels, age-at-onset, MMSE scores, and measures of senile plaque density) no evidence was found supporting a role for these particular variants in AD. More detailed studies of regional linkage disequilibrium structure around CTNNA3 will likely be required to determine whether sequence variation in this region impacts AD.
Journal of Cellular and Molecular Medicine, Dec 1, 2009
The blood-brain barrier (BBB) is a tightly controlled semi-permeable barrier which prevents the p... more The blood-brain barrier (BBB) is a tightly controlled semi-permeable barrier which prevents the paracellular passage for macro-molecules and cells from the blood stream into the brain [1]. It consists primarily of capillary endothelial cells packed together by tight junctions (TJs), together with the adjoining astrocyte endfeet and pericytes. TJs are specialized membrane domains at the most apical region of epithelial and endothelial cells, involved in both prevention of solute and water leakage (barrier function) and maintenance of cellular polarity (fence function) [2]. In the brain of vertebrates there are two types of cells which are known to bear TJs or TJs-like structures: vascular endothelial cells and oligodendrocytes [3]. TJs networks are formed by integral membrane proteins, such as junctional associated membrane protein 1 [4],
Objectives: The purpose of the present study was to investigate patterns of personality in patien... more Objectives: The purpose of the present study was to investigate patterns of personality in patients with subjective cognitive impairment (SCI) and mild cognitive impairment (MCI), compared to healthy controls. Methods: We assessed24 patients with SCI, 35 patients with MCI and 26 healthy controls with the self-report questionnaire Swedish Universities Scales of Personality measuring aspects of neuroticism/anxiety proneness, extraversion, and aggression-hostility. Results: Patients with SCI and MCI showed significantly more Somatic Trait Anxiety, Psychic Trait Anxiety and Stress Susceptibility than healthy controls. Moreover, there was a significant increase in Detachment in patients with MCI and a significant decrease in Adventure Seeking in patients with SCI, relative to healthy controls. Conclusions: Patients with SCI and MCI presented specific patterns of personality alterations with higher scores in traits related to anxiety proneness and aggression-hostility and lower in traits of extraversion. In most subscales differences followed a sequential pattern with gradually increasing scores from healthy controls, to patients with SCI and further to MCI. The groups differed in amount and type of symptoms, suggesting that patterns of personality may be related to degree of cognitive impairment.
The presynaptically located γ-aminobutyric acid (GABA) transporter (GAT-1) was studied in a group... more The presynaptically located γ-aminobutyric acid (GABA) transporter (GAT-1) was studied in a group of patients with Alzheimer's disease (AD) and in a control group using the GAT-1 selective radioligand [ 3 H]tiagabine. Post mortem brain tissue from frontal cortex, temporal cortex, and caudate nucleus from 18 AD patients and 23 age-matched controls were studied. The binding was saturable (Kd 26 nM) and region specific. There were no significant differences between the groups with respect to the binding capacity (Bmax) and binding affinity (Kd). The unaltered [ 3 H]tiagabine binding to GAT-1 protein indicates that intrinsic GABA neurons are spared in Alzheimer's disease.
Most genetic sequence variants that contribute to variability in complex human traits will have s... more Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004-April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) beta-amyloid (Abeta) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.
American Journal of Medical Genetics - Neuropsychiatric Genetics, Dec 28, 2007
Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several epidemiological... more Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several epidemiological and biochemical features. The present study aimed to assess the possible influence of the AMD-associated complement factor H (CFH) Y402H (1277T > C) polymorphism on the risk of AD. Caucasian subjects (n ¼ 800) meeting the criteria for probable (n ¼ 717) or definite (n ¼ 83) AD and Caucasian non-demented controls (n ¼ 1265) were included in this multi-center casecontrol study, in which genotype and allele frequencies of the CFH 1277T > C polymorphism were determined and related to diagnosis, APOE genotype, Mini-Mental State Examination score (MMSE) and the cerebrospinal fluid (CSF) biomarkers total-tau (T-tau), phospho-tau 181 (P-tau 181), and b-amyloid 1-42 (Ab 1-42). The AMDassociated CFH genotypes (1277CC and 1277TC) were overrepresented in subjects with AD as compared to control individuals (P ¼ 0.029). Positive C carrier status was associated with an odds ratio (OR) for AD of 1.24 (95% confidence interval [CI] 1.02-1.50). When APOE e4 carrier status was included in the regression model, this association was even stronger (OR 1.34, 95% CI: 1.08-1.65, P ¼ 0.007). Subgroup analysis showed that the association between CFH C allele positivity and AD was only evident for individuals carrying the APOE e4 allele. Positive C carrier status was also associated with lower levels of CSF Ab 1-42 selectively in the control group in an APOE e4-independent manner (P ¼ 0.003). In conclusion, the CFH 1277T > C polymorphism seems to influence the risk of AD and there appears to be an interaction between CFH 1277C and APOE e4 alleles. The CFH 1277C allele may predispose patients for co-morbidity in AD and AMD.
The -amyloid peptide (A) is a major component of Alzheimer disease (AD)-associated senile plaqu... more The -amyloid peptide (A) is a major component of Alzheimer disease (AD)-associated senile plaques and is generated by sequential cleavage of the -amyloid precursor protein (APP) by -secretase (BACE1) and ␥-secretase. BACE1 cleaves APP at the N terminus of the A domain, generating a membrane-bound C-terminal fragment (CTF-) that can be subsequently cleaved by ␥-secretase within the transmembrane domain to release A. Because BACE1 initiates A generation, it represents a potential target molecule to interfere with A production in therapeutic strategies for AD. BACE1 interacts with Golgi-localized, ␥-ear-containing, ADP ribosylation factor-binding (GGA) proteins that are involved in the subcellular trafficking of BACE1. Here, we show that GGA1 is preferentially expressed in neurons of the human brain. GGA1 was also detected in activated microglia surrounding amyloid plaques in AD brains. Functional analyses with cultured cells demonstrate that GGA1 is implicated in the proteolytic processing of APP. Overexpression of GGA1 or a dominant-negative variant reduced cleavage of APP by BACE1 as indicated by a decrease in CTF- generation. Importantly, overexpression of GGA1 reduced, whereas RNAi-mediated suppression of GGA1 increased the secretion of A. The modulation of APP processing by GGA1 is independent of a direct interaction of both proteins. Because total cellular activity of BACE1 was not affected by GGA1 expression, our data indicate that changes in the subcellular trafficking of BACE1 or other GGA1-dependent proteins contribute to changes in APP processing and A generation. Thus, GGA proteins might be involved in the pathogenesis of AD.
The endocytic pathway is important in amyloid precursor protein (APP) processing and β‐amyloid fo... more The endocytic pathway is important in amyloid precursor protein (APP) processing and β‐amyloid formation. Our studies have shown that endocytic pathway activation is a prominent and early feature of neurons in vulnerable regions of the brain in sporadic Alzheimer's disease. We report that endocytic pathway abnormalities are present not only in neurons, but in cerebral endothelia in Alzheimer's disease caused by certain APP mutations. The presence or absence of endocytic abnormalities distinguish subtypes of familial Alzheimer's disease linked to APP mutations from presenilin mutations, supporting the notion that different cellular pathways are involved in the altered processing of APP leading to increased β‐amyloid generation in certain of these different Alzheimer's disease subtypes.
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Papers by Nenad Bogdanovic