Disease modifying therapy for AD?

被引:103
作者
Golde, Todd E. [1 ]
机构
[1] Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA
关键词
D O I
10.1111/j.1471-4159.2006.04211.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Alzheimer's disease (AD) is the most common form of dementia in industrialized nations. If more effective therapies are not developed that either prevent AD or block progression of the disease in its very early stages, the economic and societal cost of caring for AD patients will be devastating. Only two types of drugs are currently approved for the treatment of AD: inhibitors of acetyl cholinesterase, which symptomatically enhance cognitive state to some degree but are not disease modifying; and the adamantane derivative, memantine. Memantine preferentially blocks excessive NMDA receptor activity without disrupting normal receptor activity and is thought to be a neuroprotective agent that blocks excitotoxicty. Memantine therefore may have a potentially disease modifying effect in multiple neurodegenerative conditions. An improved understanding of the pathogeneses of AD has now led to the identification of numerous therapeutic targets designed to alter amyloid beta protein (A beta) or tau accumulation. Therapies that alter A beta and tau through these various targets are likely to have significant disease modifying effects. Many of these targets have been validated in proof of concept studies in preclinical animal models, and some potentially disease modifying therapies targeting A beta or tau are being tested in the clinic. This review will highlight both the promise of and the obstacles to developing such disease modifying AD therapies.
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收藏
页码:689 / 707
页数:19
相关论文
共 246 条
[51]   Elevated amyloid β protein (Aβ42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene [J].
Ertekin-Taner, N ;
Ronald, J ;
Feuk, L ;
Prince, J ;
Tucker, M ;
Younkin, L ;
Hella, M ;
Jain, S ;
Hackett, A ;
Scanlin, L ;
Kelly, J ;
Kihiko-Ehman, M ;
Neltner, M ;
Hersh, L ;
Kindy, M ;
Markesbery, W ;
Hutton, M ;
de Andrade, M ;
Petersen, RC ;
Graff-Radford, N ;
Estus, S ;
Brookes, AJ ;
Younkin, SG .
HUMAN MOLECULAR GENETICS, 2005, 14 (03) :447-460
[52]   CLEAVAGE OF AMYLOID-BETA PEPTIDE DURING CONSTITUTIVE PROCESSING OF ITS PRECURSOR [J].
ESCH, FS ;
KEIM, PS ;
BEATTIE, EC ;
BLACHER, RW ;
CULWELL, AR ;
OLTERSDORF, T ;
MCCLURE, D ;
WARD, PJ .
SCIENCE, 1990, 248 (4959) :1122-1124
[53]   Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1 [J].
Esler, WP ;
Kimberly, WT ;
Ostaszewski, BL ;
Diehl, TS ;
Moore, CL ;
Tsai, JY ;
Rahmati, T ;
Xia, WM ;
Selkoe, DJ ;
Wolfe, MS .
NATURE CELL BIOLOGY, 2000, 2 (07) :428-434
[54]   Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans [J].
Fagan, AM ;
Mintun, MA ;
Mach, RH ;
Lee, SY ;
Dence, CS ;
Shah, AR ;
LaRossa, GN ;
Spinner, ML ;
Klunk, WE ;
Mathis, CA ;
DeKosky, ST ;
Morris, JC ;
Holtzman, DM .
ANNALS OF NEUROLOGY, 2006, 59 (03) :512-519
[55]  
Fahrenholz F, 2000, ANN NY ACAD SCI, V920, P215
[56]   Lithium chloride increases the production of amyloid-β peptide independently from its inhibition of glycogen synthase kinase 3 [J].
Feyt, C ;
Kienlen-Campard, P ;
Leroy, K ;
N'Kuli, F ;
Courtoy, PJ ;
Brion, JP ;
Octave, JN .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (39) :33220-33227
[57]   Effects of Aβ immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease [J].
Fox, NC ;
Black, RS ;
Gilman, S ;
Rossor, MN ;
Griffith, SG ;
Jenkins, L ;
Koller, M .
NEUROLOGY, 2005, 64 (09) :1563-1572
[58]   Imaging of onset and progression of Alzheimer's disease with voxel-compression mapping of serial magnetic resonance images [J].
Fox, NC ;
Crum, WR ;
Scahill, RI ;
Stevens, JM ;
Janssen, JC ;
Rossor, MN .
LANCET, 2001, 358 (9277) :201-205
[59]   γ-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site [J].
Fraering, PC ;
Ye, WJ ;
LaVoie, MJ ;
Ostaszewski, BL ;
Selkoe, DJ ;
Wolfe, MS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (51) :41987-41996
[60]   Phenolic anti-inflammatory antioxidant reversal of Aβ-induced cognitive deficits and neuropathology [J].
Frautschy, SA ;
Hu, W ;
Kim, P ;
Miller, SA ;
Chu, T ;
Harris-White, ME ;
Cole, GM .
NEUROBIOLOGY OF AGING, 2001, 22 (06) :993-1005