Alzheimer Disease: Wang N

Kolstoe SE, Ridha BH, Bellotti V, Wang N, Robinson CV, Crutch SJ, Keir G, Kukkastenvehmas R, Gallimore JR, Hutchinson WL, Hawkins PN, Wood SP, Rossor MN, Pepys MB. · Centre for Amyloidosis and Acute Phase Proteins and National Amyloidosis Centre, Division of Medicine (Royal Free Campus), University College London Medical School, London NW3 2PF, United Kingdom. · Proc Natl Acad Sci U S A. · Pubmed #19372378 links to  free full text

Abstract: New therapeutic approaches in Alzheimer's disease are urgently needed. The normal plasma protein, serum amyloid P component (SAP), is always present in cerebrospinal fluid (CSF) and in the pathognomonic lesions of Alzheimer's disease, cerebrovascular and intracerebral Abeta amyloid plaques and neurofibrillary tangles, as a result of its binding to amyloid fibrils and to paired helical filaments, respectively. SAP itself may also be directly neurocytotoxic. Here, in this unique study in Alzheimer's disease of the bis(d-proline) compound, (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), we observed depletion of circulating SAP and also remarkable, almost complete, disappearance of SAP from the CSF. We demonstrate that SAP depletion in vivo is caused by CPHPC cross-linking pairs of SAP molecules in solution to form complexes that are immediately cleared from the plasma. We have also solved the structure of SAP complexed with phosphothreonine, its likely ligand on hyperphosphorylated tau protein. These results support further clinical study of SAP depletion in Alzheimer's disease and potentially other neurodegenerative diseases.

Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D, McKhann G, Yan SD. · Department of Surgery, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA. · FASEB J. · Pubmed #16210396 links to  free full text

Abstract: Although amyloid-beta peptide (Abeta) is the neurotoxic species implicated in the pathogenesis of Alzheimer's disease (AD), mechanisms through which intracellular Abeta impairs cellular properties, resulting in neuronal dysfunction, remain to be clarified. Here we demonstrate that intracellular Abeta is present in mitochondria from brains of transgenic mice with targeted neuronal overexpression of mutant human amyloid precursor protein and AD patients. Abeta progressively accumulates in mitochondria and is associated with diminished enzymatic activity of respiratory chain complexes (III and IV) and a reduction in the rate of oxygen consumption. Importantly, mitochondria-associated Abeta, principally Abeta42, was detected as early as 4 months, before extensive extracellular Abeta deposits. Our studies delineate a new means through which Abeta potentially impairs neuronal energetics, contributing to cellular dysfunction in AD.

Zhong Z, Qu Z, Wang N, Wang J, Xie Z, Zhang F, Zhang W, Lu Z. · Guangxi College of TCM, Nanning 530001. · Zhong Yao Cai. · Pubmed #15981887 No free full text.

Abstract: OBJECTIVE: To observe the protective effect of Panax notoginseng saponins (PNS) against pathological lesion of cholinergic neuron in rat model with Alzheimer' s disease (AD). METHODS: The AD rat model was established by intra-peritoneal injection of D-galactose combined with excitatory neurotoxin ibotenic acid (IBA) injection into bilateral nbM. The activity and content of choline acetyltransferase (ChAT), the cell morphology and number of cholinergic neuron in brain were determined by immunohistochemistry analysis. RESULTS: PNS could reduce the pathological lesion of cholinergic neuron, including the level of ChAT and number of cholinergic neuron, as compared with those of model group's rats. CONCLUSION: PNS plays a protective role in pathological lesion of cholinergic neuron in AD rat model.

Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue LF, Walker DG, Kuppusamy P, Zewier ZL, Arancio O, Stern D, Yan SS, Wu H. · Center for Reproductive Sciences and Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA. · Science. · Pubmed #15087549 links to  free full text

Abstract: Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Abeta-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Abeta to mitochondrial toxicity. Abeta interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Abeta-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Abeta interaction and suppresses Abeta-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Abeta-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Abeta interaction may be a therapeutic target in AD.