Alzheimer Disease: Ma L

Miyoshi K, Ohyagi Y, Sakae N, Motomura K, Ma L, Taniwaki T, Furuya H, Tabira T, Kira J. · Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · J Alzheimers Dis. · Pubmed #19276550 No free full text.

Abstract: Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease. Acceleration of apoptosis is one of the major pathogenic mechanisms of PS1 mutants, and PS1 mutants have also been reported to induce overproduction of amyloid-beta protein 42. Here, we investigated aberrancy in activation of initiator caspases related to two PS1 gene mutations, I143T and G384A. Acceleration of apoptosis, elevation of caspase-3/7 activity, and significant increases in caspase-4, -8 and -9 activities during apoptosis induced by several agents were found in these mutant PS1-transfected cells. Interestingly, thapsigargin treatment enhanced caspase-4 and -9 activities in I143T-mutant PS1-transfected cells, while hydrogen peroxide treatment enhanced caspase-4, -8 and -9 activities in G384A-mutant PS1-transfected cells, indicating diverse apoptosis-promoting effects of PS1 gene mutations. In addition, treatment with a beta-secretase inhibitor or gamma-secretase inhibitor significantly attenuated the effects of the PS1 mutants on caspase-3/7 activation and recovered cell viability. Our present data suggest that these PS1 mutants accelerate the activation of initiator caspases and promote apoptosis, which may be associated, at least in part, with amyloid-beta production.

Carrasquillo MM, Zou F, Pankratz VS, Wilcox SL, Ma L, Walker LP, Younkin SG, Younkin CS, Younkin LH, Bisceglio GD, Ertekin-Taner N, Crook JE, Dickson DW, Petersen RC, Graff-Radford NR, Younkin SG. · Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA. · Nat Genet. · Pubmed #19136949 No free full text.

Abstract: By analyzing late-onset Alzheimer's disease (LOAD) in a genome-wide association study (313,504 SNPs, three series, 844 cases and 1,255 controls) and evaluating the 25 SNPs with the most significant allelic association in four additional series (1,547 cases and 1,209 controls), we identified a SNP (rs5984894) on Xq21.3 in PCDH11X that is strongly associated with LOAD in individuals of European descent from the United States. Analysis of rs5984894 by multivariable logistic regression adjusted for sex gave global P values of 5.7 x 10(-5) in stage 1, 4.8 x 10(-6) in stage 2 and 3.9 x 10(-12) in the combined data. Odds ratios were 1.75 (95% CI = 1.42-2.16) for female homozygotes (P = 2.0 x 10(-7)) and 1.26 (95% CI = 1.05-1.51) for female heterozygotes (P = 0.01) compared to female noncarriers. For male hemizygotes (P = 0.07) compared to male noncarriers, the odds ratio was 1.18 (95% CI = 0.99-1.41).

Hirata-Fukae C, Li HF, Ma L, Hoe HS, Rebeck GW, Aisen PS, Matsuoka Y. · Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA. · Neurosci Lett. · Pubmed #19022346 No free full text.

Abstract: The clinical progression of Alzheimer's disease is closely related to tau pathology. Hyperphosphorylation of tau precedes histopathological evidence of tangle formation, and modulation of tau phosphorylation is a promising therapeutic target. Although some phosphorylation sites are more critical in pathological processes, the importance of each phosphorylation site is unclear. In this study, we found that levels of phosphorylated tau drastically increased in crude and insoluble tau fractions with aging in a transgenic mouse model of Alzheimer-type tauopathy. However, changes in the soluble tau fraction were minor and phosphorylation at some sites was even reduced with aging. Total soluble (presumably functional) tau was reduced, while insoluble tau increased with aging. Synaptic proteins were reduced as insoluble tau increased. Taken together, these findings suggest that levels of soluble and insoluble tau are indicative of overall levels of tau phosphorylation, and may be useful markers to evaluate the effects of anti-tau therapeutic strategies in vivo.

Matsuoka Y, Jouroukhin Y, Gray AJ, Ma L, Hirata-Fukae C, Li HF, Feng L, Lecanu L, Walker BR, Planel E, Arancio O, Gozes I, Aisen PS. · Department of Neurology, Georgetown University Medical Center, 4000 Reservoir Road N.W., Washington, DC 20057, USA. · J Pharmacol Exp Ther. · Pubmed #18199809 links to  free full text

Abstract: Neurofibrillary tangles composed of aggregated, hyperphosphorylated tau in an abnormal conformation represent one of the major pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. However, recent data suggest that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles. In the earliest stages of tauopathy, tau detaches from microtubules and accumulates in the cytosol of the somatodendritic compartment of cells. Either as a cause or an effect, tau becomes hyperphosphorylated and aggregates into paired helical filaments that comprise the tangles. To assess whether an agent that modulates microtubule function can inhibit the pathogenic process and prevent cognitive deficits in a transgenic mouse model with AD-relevant tau pathology, we administered the neuronal tubulin-preferring agent, NAPVSIPQ (NAP). Three months of treatment with NAP at an early-to-moderate stage of tauopathy reduced the levels of hyperphosphorylated soluble and insoluble tau. A 6-month course of treatment improved cognitive function. Although nonspecific tubulin-interacting agents commonly used for cancer therapy are associated with adverse effects due to their anti-mitotic activity, no adverse effects were found after 6 months of exposure to NAP. Our results suggest that neuronal microtubule interacting agents such as NAP may be useful therapeutic agents for the treatment or prevention of tauopathies.

Ohyagi Y, Miyoshi K, Ma L, Motomura K, Kira J. · Department School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Japan. · Nihon Shinkei Seishin Yakurigaku Zasshi. · Pubmed #17515111 No free full text.

Abstract: Inhibition of aggregation of amyloid p-protein (AP) and promotion of extracellular AM removal are known as potent therapeutic tools for Alzheimer's disease (AD). While, the importance of Af342 accumulating in neurons has recently been suggested, and we have reported that A/42 accumulating in the neurons moves into the nucleus, activating p53 mRNA expression and leading to apoptosis (Ohyagi et al, FASEB J, 2005). Moreover, intraneuronal Ap is reported to induce mitochondrial dysfunction via binding ABAD, synaptic pathology, and inhibition of proteasome. Thus, it is an alternative therapeutic tool to decrease the levels of A342 and p53 proteins in AD neurons. We established a human neuroblastoma (SH-SY5Y) cell culture system in which AV peptide is artificially accumulated in cytosol. We have found that apomorphine hydrochloride promotes degradation of intracellular AM and p53 attenuating oxidative stress-induced apoptosis. Using a proteasome activity assay method, one of the mechanisms is thought to be activation of proteasome. Similar anti-apoptotic effect was observed in the primary cultured neurons. Apomorphine hydrochloride is now used as a dopamine agonist for Parkinson's disease or an anti-ED drug in western countries, but also may be one of the candidate drugs to inhibit neuronal death in AD.

Wen H, Zhou Y, Lin C, Ge H, Ma L, Wang Z, Peng W, Song H. · School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China. · Bioorg Med Chem Lett. · Pubmed #17317172 No free full text.

Abstract: A new class of inhibitors of acetylcholinesterase (methyl 2-(2-(4-formylphenoxy)acetamido)-2-substituted acetate derivatives) is described. Compounds 4b and 4i were found to be more potent than galanthamine in inhibiting acetylcholinesterase.

Majercak J, Ray WJ, Espeseth A, Simon A, Shi XP, Wolffe C, Getty K, Marine S, Stec E, Ferrer M, Strulovici B, Bartz S, Gates A, Xu M, Huang Q, Ma L, Shughrue P, Burchard J, Colussi D, Pietrak B, Kahana J, Beher D, Rosahl T, Shearman M, Hazuda D, Sachs AB, Koblan KS, Seabrook GR, Stone DJ. · Department of Alzheimer's Research, Merck & Co., Inc., West Point, PA 19486, USA. · Proc Natl Acad Sci U S A. · Pubmed #17098871 links to  free full text

Abstract: Rare familial forms of Alzheimer's disease (AD) are thought to be caused by elevated proteolytic production of the Abeta42 peptide from the beta-amyloid-precursor protein (APP). Although the pathogenesis of the more common late-onset AD (LOAD) is not understood, BACE1, the protease that cleaves APP to generate the N terminus of Abeta42, is more active in patients with LOAD, suggesting that increased amyloid production processing might also contribute to the sporadic disease. Using high-throughput siRNA screening technology, we assessed 15,200 genes for their role in Abeta42 secretion and identified leucine-rich repeat transmembrane 3 (LRRTM3) as a neuronal gene that promotes APP processing by BACE1. siRNAs targeting LRRTM3 inhibit the secretion of Abeta40, Abeta42, and sAPPbeta, the N-terminal APP fragment produced by BACE1 cleavage, from cultured cells and primary neurons by up to 60%, whereas overexpression increases Abeta secretion. LRRTM3 is expressed nearly exclusively in the nervous system, including regions affected during AD, such as the dentate gyrus. Furthermore, LRRTM3 maps to a region of chromosome 10 linked to both LOAD and elevated plasma Abeta42, and is structurally similar to a family of neuronal receptors that includes the NOGO receptor, an inhibitor of neuronal regeneration and APP processing. Thus, LRRTM3 is a functional and positional candidate gene for AD, and, given its receptor-like structure and restricted expression, a potential therapeutic target.

Ikonen M, Liu B, Hashimoto Y, Ma L, Lee KW, Niikura T, Nishimoto I, Cohen P. · Department of Pediatrics, Mattel Children's Hospital, University of California, Los Angeles, CA 90095. · Proc Natl Acad Sci U S A. · Pubmed #14561895 links to  free full text

Abstract: Insulin-like growth factor-binding protein-3 (IGFBP-3) regulates IGF bioactivity and also independently modulates cell growth and survival. By using a yeast two-hybrid screen to identify IGFBP-3-interacting proteins, we cloned humanin (HN) as an IGFBP-3-binding partner. HN is a 24-aa peptide that has been shown to specifically inhibit neuronal cell death induced by familial Alzheimer's disease mutant genes and amyloid-beta (Abeta). The physical interaction of HN with IGFBP-3 was determined to be of high affinity and specificity and was confirmed by yeast mating, displaceable pull-down experiments with (His)-6-tagged HN, and ligand blot experiments. Co-immunoprecipitation of IGFBP-3 and HN from mouse testes confirmed the interaction in vivo. In cross-linking experiments, HN bound IGFBP-3 but did not compete with IGF-I-IGFBP-3 binding; competitive ligand dot blot experiments revealed the 18-aa heparin-binding domain of IGFBP-3 as the binding site for HN. Alanine scanning determined that F6A-HN mutant does not bind IGFBP-3. HN but not F6A-HN inhibited IGFBP-3-induced apoptosis in human glioblastoma-A172. In contrast, HN did not suppress IGFBP-3 response in SH-SY5Y neuroblastoma and mouse cortical primary neurons. In primary neurons, IGFBP-3 markedly potentiated HN rescue ability from Abeta1-43 toxicity. In summary, we have identified an interaction between the survival peptide HN and IGFBP-3 that is pleiotrophic in nature and is capable of both synergistic and antagonistic interaction. This interaction may prove to be important in neurological disease processes and could provide important targets for drug development.

Figueroa DJ, Morris JA, Ma L, Kandpal G, Chen E, Li YM, Austin CP. · Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. · Neurobiol Dis. · Pubmed #11848684 No free full text.

Abstract: Demonstration that cleavage of both APP and Notch are dependent on the product of the early onset Alzheimer's disease gene, presenilin-1 (PS1), has raised the possibility that Notch function may be altered in AD. This finding also suggests that Notch may be affected by APPgamma-secretase inhibitors under development for the treatment of Alzheimer's disease, as these target PS1. Data that address these questions have been lacking, due to inability to specifically modulate PS1 activity in a system directly relevant to the adult human brain. Using novel highly specific inhibitors of PS1/gamma-secretase, we demonstrate that modulation of PS1 activity in human CNS neurons not only affects Abeta generation, but also has unanticipated effects on Notch and its activity. We demonstrate that intracellular trafficking of Notch in human CNS neurons is altered by inhibition of PS1 and is accompanied by dramatic changes in neurite morphology, consistent with inhibition of Notch activity. These data, together with immunohistochemical evidence of elevation of Notch pathway expression in AD brain, suggest that Notch dysregulation may contribute to the neuritic dystrophy characteristically seen in Alzheimer's disease brain. In addition, they raise the possibility that inhibition of gamma-secretase/PS1 may have clinically beneficial effects on the neuritic pathology of AD, in addition to its expected effect to reduce amyloid burden.