Alzheimer's disease: strategies for disease modification

被引:888
作者
Citron, Martin [1 ]
机构
[1] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA
关键词
AMYLOID-BETA-PEPTIDE; POSITRON-EMISSION-TOMOGRAPHY; GAMMA-SECRETASE INHIBITOR; A-BETA; APOLIPOPROTEIN-E; MOUSE MODEL; MEMORY DEFICITS; ANIMAL-MODEL; DOUBLE-BLIND; FOLLOW-UP;
D O I
10.1038/nrd2896
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Alzheimer's disease is the largest unmet medical need in neurology. Current drugs improve symptoms, but do not have profound disease-modifying effects. However, in recent years, several approaches aimed at inhibiting disease progression have advanced to clinical trials. Among these, strategies targeting the production and clearance of the amyloid-beta peptide - a cardinal feature of Alzheimer's disease that is thought to be important in disease pathogenesis - are the most advanced. Approaches aimed at modulating the abnormal aggregation of tau filaments (another key feature of the disease), and those targeting metabolic dysfunction, are also being evaluated in the clinic. This article discusses recent progress with each of these strategies, with a focus on anti-amyloid strategies, highlighting the lessons learned and the challenges that remain.
引用
收藏
页码:387 / 398
页数:12
相关论文
共 105 条
[41]   BACE1 (β-secretase) transgenic neurochernical deficits ind knockout mice:: identification of and behavioral changes [J].
Harrison, SM ;
Harper, AJ ;
Hawkins, J ;
Duddy, G ;
Grau, E ;
Pugh, PL ;
Winter, PH ;
Shilliam, CS ;
Hughes, ZA ;
Dawson, LA ;
Gonzalez, MI ;
Upton, N ;
Pangalos, MN ;
Dingwall, C .
MOLECULAR AND CELLULAR NEUROSCIENCE, 2003, 24 (03) :646-655
[42]   PPARs in the brain [J].
Heneka, Michael T. ;
Landreth, Gary E. .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2007, 1771 (08) :1031-1045
[43]   Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of Aβ42 in patients with Alzheimer's disease [J].
Hock, C ;
Maddalena, A ;
Raschig, A ;
Müller-Spahn, F ;
Eschweiler, G ;
Hager, K ;
Heuser, I ;
Hampel, H ;
Müller-Thomsen, T ;
Oertel, W ;
Wienrich, M ;
Signorell, A ;
Gonzalez-Agosti, C ;
Nitsch, RM .
AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS, 2003, 10 (01) :1-6
[44]   Long-term effects of Aβ42 immunisation in Alzheimer's disease:: follow-up of a randomised, placebo-controlled phase I trial [J].
Holmes, Clive ;
Boche, Delphine ;
Wilkinson, David ;
Yadegarfar, Ghasem ;
Hopkins, Vivienne ;
Bayer, Anthony ;
Jones, Roy W. ;
Bullock, Roger ;
Love, Seth ;
Neal, James W. ;
Zotova, Elina ;
Nicoll, James A. R. .
LANCET, 2008, 372 (9634) :216-223
[45]   Antibody-mediated resolution of light chain-associated amyloid deposits [J].
Hrncic, R ;
Wall, J ;
Wolfenbarger, DA ;
Murphy, CL ;
Schell, M ;
Weiss, DT ;
Solomon, A .
AMERICAN JOURNAL OF PATHOLOGY, 2000, 157 (04) :1239-1246
[46]   Correlative memory deficits, A beta elevation, and amyloid plaques in transgenic mice [J].
Hsiao, K ;
Chapman, P ;
Nilsen, S ;
Eckman, C ;
Harigaya, Y ;
Younkin, S ;
Yang, FS ;
Cole, G .
SCIENCE, 1996, 274 (5284) :99-102
[47]   Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves [J].
Hu, Xiangyou ;
He, Wanxia ;
Diaconu, Claudiu ;
Tang, Xiaoying ;
Kidd, Grahame J. ;
Macklin, Wendy B. ;
Trapp, Bruce D. ;
Yan, Riqiang .
FASEB JOURNAL, 2008, 22 (08) :2970-2980
[48]   Bace1 modulates myelination in the central and peripheral nervous system [J].
Hu, Xiangyou ;
Hicks, Caitlin W. ;
He, Wanxia ;
Wong, Philip ;
Macklin, Wendy B. ;
Trapp, Bruce D. ;
Yan, Riqiang .
NATURE NEUROSCIENCE, 2006, 9 (12) :1520-1525
[49]   Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 [J].
Hutton, M ;
Lendon, CL ;
Rizzu, P ;
Baker, M ;
Froelich, S ;
Houlden, H ;
Pickering-Brown, S ;
Chakraverty, S ;
Isaacs, A ;
Grover, A ;
Hackett, J ;
Adamson, J ;
Lincoln, S ;
Dickson, D ;
Davies, P ;
Petersen, RC ;
Stevens, M ;
de Graaff, E ;
Wauters, E ;
van Baren, J ;
Hillebrand, M ;
Joosse, M ;
Kwon, JM ;
Nowotny, P ;
Che, LK ;
Norton, J ;
Morris, JC ;
Reed, LA ;
Trojanowski, J ;
Basun, H ;
Lannfelt, L ;
Neystat, M ;
Fahn, S ;
Dark, F ;
Tannenberg, T ;
Dodd, PR ;
Hayward, N ;
Kwok, JBJ ;
Schofield, PR ;
Andreadis, A ;
Snowden, J ;
Craufurd, D ;
Neary, D ;
Owen, F ;
Oostra, BA ;
Hardy, J ;
Goate, A ;
van Swieten, J ;
Mann, D ;
Lynch, T .
NATURE, 1998, 393 (6686) :702-705
[50]  
Imbimbo B.P., 2008, Drug Discovery Today: Therapeutic Strategies, V5, P169, DOI DOI 10.1016/J.DDSTR.2008.10.002