Presenilins as therapeutic targets for the treatment of Alzheimer's disease

被引：42

作者：

Golde, TE ^{[1
]}

Younkin, SG ^{[1
]}

机构：

[1] Mayo Clin Jacksonville, Dept Neurosci, Jacksonville, FL 32224 USA

来源：

TRENDS IN MOLECULAR MEDICINE | 2001年 / 7卷 / 06期

关键词：

D O I：

10.1016/S1471-4914(01)02064-0

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：

Studies demonstrating that accumulation and aggregation of the amyloid beta protein (A beta) within the brain is likely to cause Alzheimer's disease (AD) have provided the rationale for therapeutic strategies aimed at influencing A beta production, aggregation and clearance. gamma -secretase catalyzes the final cleavage that releases the A beta from its precursor; therefore, it is a potential therapeutic target for the treatment of AD. Recent data show that the polytopic membrane proteins presenilin 1 and presenilin 2 are either catalytic components or essential co-factors of a membrane-bound proteolytic complex that possesses gamma -secretase activity, Although recent findings demonstrating that gamma -secretase inhibitors bind directly to presenilins (PSs) further support a catalytic role for PSs in gamma -secretase cleavage, additional studies ate still needed to clarify the role of PSs in gamma -secretase cleavage and the use of targeting PSs to reduce A beta production.

引用

页码：264 / 269

页数：6

共 52 条

[11] Review: Neurobiology - The presenilins in Alzheimer's disease - Proteolysis holds the key [J].

Haass, C ;

De Strooper, B .

SCIENCE, 1999, 286 (5441) :916-919

[12] Amyloid, the presenilins and Alzheimer's disease [J].

Hardy, J .

TRENDS IN NEUROSCIENCES, 1997, 20 (04) :154-159

[13]

HAUGABOOK SJ, 2000, FASEB J

[14] Total inactivation of γ-secretase activity in presenilin-deficient embryonic stem cells [J].

Herreman, A ;

Serneels, L ;

Annaert, W ;

Collen, D ;

Schoonjans, L ;

De Strooper, B .

NATURE CELL BIOLOGY, 2000, 2 (07) :461-462

[15] Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency [J].

Herreman, A ;

Hartmann, D ;

Annaert, W ;

Saftig, P ;

Craessaerts, K ;

Serneels, L ;

Umans, L ;

Schrijvers, V ;

Checler, F ;

Vanderstichele, H ;

Baekelandt, V ;

Dressel, R ;

Cupers, P ;

Huylebroeck, D ;

Zwijsen, A ;

Van Leuven, F ;

De Strooper, B .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (21) :11872-11877

[16] Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor [J].

Hong, L ;

Koelsch, G ;

Lin, XL ;

Wu, SL ;

Terzyan, S ;

Ghosh, AK ;

Zhang, XC ;

Tang, J .

SCIENCE, 2000, 290 (5489) :150-153

[17] Identification of a novel aspartic protease (Asp 2) as β-secretase [J].

Hussain, I ;

Powell, D ;

Howlett, DR ;

Tew, DG ;

Week, TD ;

Chapman, C ;

Gloger, IS ;

Murphy, KE ;

Southan, CD ;

Ryan, DM ;

Smith, TS ;

Simmons, DL ;

Walsh, FS ;

Dingwall, C ;

Christie, G .

MOLECULAR AND CELLULAR NEUROSCIENCE, 1999, 14 (06) :419-427

[18] DEPOSITION OF BETA/A4 IMMUNOREACTIVITY AND NEURONAL PATHOLOGY IN TRANSGENIC MICE EXPRESSING THE CARBOXYL-TERMINAL FRAGMENT OF THE ALZHEIMER AMYLOID PRECURSOR IN THE BRAIN [J].

KAMMESHEIDT, A ;

BOYCE, FM ;

SPANOYANNIS, AF ;

CUMMINGS, BJ ;

ORTEGON, M ;

COTMAN, C ;

VAUGHT, JL ;

NEVE, RL .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (22) :10857-10861

[19] Separation of presenilin function in amyloid β-peptide generation and endoproteolysis of Notch [J].

Kulic, L ;

Walter, J ;

Multhaup, G ;

Teplow, DB ;

Baumeister, R ;

Romig, H ;

Capell, A ;

Steiner, H ;

Haass, C .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (11) :5913-5918

[20] The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases [J].

LaPointe, CF ;

Taylor, RK .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (02) :1502-1510

← 1 2 3 4 5 6 →