The human natural killer-1 (HNK-1), 3-sulfonated glucuronic acid, is a glycoepitope marker of cel... more The human natural killer-1 (HNK-1), 3-sulfonated glucuronic acid, is a glycoepitope marker of cell adhesion that participates in cell-cell and cell-extracellular matrix interactions and in neurite growth. Very little is known about the regulation of the HNK-1 glycan in neurodegenerative disease, particularly in Alzheimer's disease (AD). In this study, we investigate changes in the levels of HNK-1 carrier glycoproteins in AD. We demonstrate an overall decrease in HNK-1 immunoreactivity in glycoproteins extracted from the frontal cortex of AD subjects, compared with levels from non-demented controls (NDC). Immunoblotting of ventricular post-mortem and lumbar ante-mortem cerebrospinal fluid with HNK-1 antibodies indicate similar levels of carrier glycoproteins in AD and NDC samples. Decrease in HNK-1 carrier glycoproteins were not paralleled by changes in messenger RNA (mRNA) levels of the enzymes involved in the synthesis of the glycoepitope, β-1,4-galactosyltransferase (β4GalT), ...
Pathogenic events in Alzheimer's disease (AD) involve an imbalance between the production and cle... more Pathogenic events in Alzheimer's disease (AD) involve an imbalance between the production and clearance of the neurotoxic β-amyloid peptide (Aβ), especially the 42 amino acid peptide Aβ1–42. While much is known about the production of Aβ1–42, many questions remain about how the peptide is degraded. To investigate the degradation pattern, we developed a method based on immunoprecipitation combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry that determines the Aβ degradation fragment pattern in cerebrospinal fluid (CSF). We found in total 18 C-terminally and 2 N-terminally truncated Aβ peptides and preliminary data indicated that there were differences in the detected Aβ relative abundance pattern between AD and healthy controls. Here, we provide direct evidence that an Aβ fragment signature consisting of Aβ1–16, Aβ1–33, Aβ1–39, and Aβ1–42 in CSF distinguishes sporadic AD patients from non-demented controls with an overall accuracy of 86%.
New therapeutic strategies in Alzheimer's disease (AD) are focused on targeting amyloid-β (Aβ... more New therapeutic strategies in Alzheimer's disease (AD) are focused on targeting amyloid-β (Aβ) to modify the underlying cause of the disease rather than just the symptoms. The aim of this study was to investigate the long-term effects of treatment with the anti-Aβ compound phenserine on (i) cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and (ii) brain metabolism as assessed by the regional cerebral metabolic rate for glucose (rCMRglc), using positron emission tomography. Twenty patients with mild AD were included in the study and after 12 months treatment with phenserine, CSF Aβ 40 and α- and β-secretase-cleaved soluble amyloid-β protein precursor (sAβPP) levels had significantly increased and rCMRglc had stabilized. Levels of CSF Aβ 40 and sAβPP correlated positively with rCMRglc and cognition while CSF Aβ 42 levels, the Aβ 42/40 ratio, P-tau, and T-tau correlated negatively with rCMRglc and cognition. In summary, long-term phenserine treatment resulted in increa...
The human natural killer-1 (HNK-1), 3-sulfonated glucuronic acid, is a glycoepitope marker of cel... more The human natural killer-1 (HNK-1), 3-sulfonated glucuronic acid, is a glycoepitope marker of cell adhesion that participates in cell-cell and cell-extracellular matrix interactions and in neurite growth. Very little is known about the regulation of the HNK-1 glycan in neurodegenerative disease, particularly in Alzheimer's disease (AD). In this study, we investigate changes in the levels of HNK-1 carrier glycoproteins in AD. We demonstrate an overall decrease in HNK-1 immunoreactivity in glycoproteins extracted from the frontal cortex of AD subjects, compared with levels from non-demented controls (NDC). Immunoblotting of ventricular post-mortem and lumbar ante-mortem cerebrospinal fluid with HNK-1 antibodies indicate similar levels of carrier glycoproteins in AD and NDC samples. Decrease in HNK-1 carrier glycoproteins were not paralleled by changes in messenger RNA (mRNA) levels of the enzymes involved in the synthesis of the glycoepitope, β-1,4-galactosyltransferase (β4GalT), ...
Pathogenic events in Alzheimer's disease (AD) involve an imbalance between the production and cle... more Pathogenic events in Alzheimer's disease (AD) involve an imbalance between the production and clearance of the neurotoxic β-amyloid peptide (Aβ), especially the 42 amino acid peptide Aβ1–42. While much is known about the production of Aβ1–42, many questions remain about how the peptide is degraded. To investigate the degradation pattern, we developed a method based on immunoprecipitation combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry that determines the Aβ degradation fragment pattern in cerebrospinal fluid (CSF). We found in total 18 C-terminally and 2 N-terminally truncated Aβ peptides and preliminary data indicated that there were differences in the detected Aβ relative abundance pattern between AD and healthy controls. Here, we provide direct evidence that an Aβ fragment signature consisting of Aβ1–16, Aβ1–33, Aβ1–39, and Aβ1–42 in CSF distinguishes sporadic AD patients from non-demented controls with an overall accuracy of 86%.
New therapeutic strategies in Alzheimer's disease (AD) are focused on targeting amyloid-β (Aβ... more New therapeutic strategies in Alzheimer's disease (AD) are focused on targeting amyloid-β (Aβ) to modify the underlying cause of the disease rather than just the symptoms. The aim of this study was to investigate the long-term effects of treatment with the anti-Aβ compound phenserine on (i) cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and (ii) brain metabolism as assessed by the regional cerebral metabolic rate for glucose (rCMRglc), using positron emission tomography. Twenty patients with mild AD were included in the study and after 12 months treatment with phenserine, CSF Aβ 40 and α- and β-secretase-cleaved soluble amyloid-β protein precursor (sAβPP) levels had significantly increased and rCMRglc had stabilized. Levels of CSF Aβ 40 and sAβPP correlated positively with rCMRglc and cognition while CSF Aβ 42 levels, the Aβ 42/40 ratio, P-tau, and T-tau correlated negatively with rCMRglc and cognition. In summary, long-term phenserine treatment resulted in increa...
Uploads
Papers