Tài liệu Báo cáo khoa học: Upregulation of the a-secretase ADAM10 – risk or reason for hope? docx

REVIEW ARTICLE

Upregulation of the a-secretase ADAM10 – risk or reason

for hope?

Kristina Endres and Falk Fahrenholz

Department of Psychiatry and Psychotherapy, Clinical Research Group, Johannes Gutenberg-University, Mainz, Germany

Identification of ADAM10 as a

functional a-secretase

A disintegrin and metalloproteinase 10 (ADAM10)

originally came into focus in genetical and biochemical

research as a peptide sequence purified from bovine

brain myelin membrane preparations [1], and was

referred to as MADM (i.e. mammalian disintegrin-me￾talloprotease). Accidentally, this metalloproteinase was

identified via an artifact resulting from in vitro studies:

it has been described as a proteinase for the cytosolic

myelin basic protein [2], which is a rather unphysiolog￾ical substrate for the type I transmembrane enzyme

ADAM10. Further studies revealed that ADAM10 is

expressed in a wide variety of tissues either in Bos

taurus [3] and, more interestingly, in distinct areas of

the human brain [4,5] and peripheral structures [6,7].

Striking similarity concerning the inhibitory profile of

ADAM10 [8] with the putative a-secretase [9] sug￾gested a more physiological role for its enzymatic

activity: overexpression of the ADAM10 cDNA in

HEK293 cells first identified its function as an amyloid

precursor protein (APP) cleaving a-secretase [8], which

subsequently was verified in vivo. Alzheimer’s disease

(AD) model mice, which were crossbred with

ADAM10 transgenic mice, revealed a strongly attenu￾ated plaque pathology and an enhanced production

of the a-secretase derived soluble cleavage product

APPs-a [10]. Furthermore, these mice had an increased

learning and memory potential [10], which might

correlate with the observed enhanced cholinergic and

Keywords

alpha-secretase; amyloid precursor protein;

Alzheimer’s disease; domain structure;

neuroprotection; shedding; synaptogenesis;

TACE

Correspondence

K. Endres and F. Fahrenholz, Department of

Psychiatry and Psychotherapy, Clinical

Research Group, Johannes Gutenberg￾University, 55131 Mainz, Germany

Fax: + 49 6131 176690

Tel: + 49 6131 172133

E-mail: [email protected].

uni-mainz.de; [email protected]

(Received 4 November 2009, revised 10

December 2009, accepted 6 January 2010)

doi:10.1111/j.1742-4658.2010.07566.x

A decade ago, a disintegrin and metalloproteinase 10 (ADAM10) was iden￾tified as an a-secretase and as a key proteinase in the processing of the amy￾loid precursor protein. Accordingly, the important role that it plays in

Alzheimer’s disease was manifested. Animal models with an overexpression

of ADAM10 revealed a beneficial profile of the metalloproteinase with

respect to learning and memory, plaque load and synaptogenesis. Therefore,

ADAM10 presents a worthwhile target with respect to the treatment of a

neurodegenerative disease such as Morbus Alzheimer. Initially, ADAM10

was suggested to be an enzyme, shaping the extracellular matrix by cleavage

of collagen type IV, or to be a tumour necrosis factor a convertase. In a rel￾atively short time, a wide variety of additional substrates (with amyloid pre￾cursor protein probably being the most prominent) has been identified and

the search is still ongoing. Hence, any side effects concerning the therapeutic

enhancement of ADAM10 a-secretase activity have to be considered. The

present review summarizes our knowledge about the structure and function

of ADAM10 and highlights the opportunities for enhancing the expression

and ⁄ or activity of the a-secretase as a therapeutic target.

Abbreviations

5-HT4, serotonin 5-hydroxytryptamine; AD, Alzheimer’s disease; ADAM, a disintegrin and metalloproteinase; APP, amyloid precursor protein;

Ab, b-amyloid protein; GPCR, G protein-coupled receptor; GPI, glycosylphosphatidylinositol; PACAP, pituitary adenylate cyclase-activating

peptide; PKC, protein kinase C; SH3, Src homology 3; TACE, tumour necrosis factor a cleaving enzyme.

FEBS Journal 277 (2010) 1585–1596 ª 2010 The Authors Journal compilation ª 2010 FEBS 1585