Γ-Secretase Inhibitors for Alzheimer’s Disease - Springer

7/25/2019 -Secretase Inhibitors for Alzheimers Disease - Springer

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http://link.springer.com/article/10.2165/00126839-200607020-00003 1/15

Review Article

Drugs in R&D

March 2006, Volume 7,Issue 2,pp 87-97

First online: 06 January 2013

-Secretase Inhibitors for Alzheimers

DiseaseBalancing Efficacy and Toxicity

Donna M. Barten

, Jere E. MeredithJr

, Robert Zaczek

, John G. Houston

, Charles F. Albright

Abstract

The amyloid hypothesis, which states that -amyloid (A) aggregates cause the

onset and progression of Alzheimers disease (AD), is a leading proposal to explain

AD aetiology. Based on this hypothesis, compounds that inhibit -secretase, one of

the enzymes responsible for forming A, are potential therapeutics for AD.

Preclinical studies clearly establish that -secretase inhibitors can reduce brain A

in rodent models. The initial investigation of the effects of a -secretase inhibitor on

A-induced cognitive deficits in transgenic mice showed that modest A

reductions (1530%) are sufficient to reverse A-induced cognitive deficits in

Tg2576 mice. Extending these studies to other -secretase inhibitors and other

models with A-induced cognitive deficits will be important. Unfortunately, -

secretase inhibitors also cause abnormalities in the gastrointestinal tract, thymus

and spleen in rodents. These changes likely result from inhibition of Notch

cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Two

recent studies in rodents suggest that A reduction using -secretase inhibitors can

be partially separated from Notch inhibition. Given the uncertain A reduction

target and the potential for mechanism-based toxicity, biomarkers for efficacy and

toxicity would be helpful in clinical trials. The first report of -secretase inhibitors

in clinical trials was recently published. In this study, LY-450139 reduced plasmaA, but not cerebrospinal fluid A . Taken together, the results of studies to date

suggest that -secretase inhibitors have the potential to address a large unmet
http://link.springer.com/journal/40268/7/2/page/1http://link.springer.com/journal/40268/7/2/page/1http://link.springer.com/journal/40268


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medical need if the technical challenges can be overcome.

A-induced Cognitive Deficit

Contextual Fear Conditioning

-secretase Inhibitor

Notch Signaling Activity

App Transgenic Mouse

CSF A Level KO Mouse

Tg2576 Mouse

Notch Inhibition

Reversal Learning

Heterozygous KO Mouse

-Secretase Activity

Plasma A Level Ad Brain

A Reduction

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About this Article

Title

-Secretase Inhibitors for Alzheimers Disease

Journal

Drugs in R&D

Volume 7, Issue 2 , pp 87-97

Cover Date

2006-03

DOI

10.2165/00126839-200607020-00003

Print ISSN

1174-5886

Online ISSN

1179-6901

Publisher

Springer International Publishing

Additional Links

Register for Journal Updates

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About This Journal

Manuscript Submission

Topics

PharmacotherapyPharmacology/Toxicology

Internal Medicine

Industry Sectors

Biotechnology

Pharma

Authors

Dr Donna M. Barten(1)

Jere E. Meredith Jr(1)

Robert Zaczek(1)
http://link.springer.com/search?facet-creator=%22Robert+Zaczek%22http://link.springer.com/search?facet-creator=%22Jere+E.+Meredith+Jr%22http://link.springer.com/search?facet-creator=%22Dr+Donna+M.+Barten%22http://link.springer.com/industry/pharmahttp://link.springer.com/industry/biotechhttp://link.springer.com/search?facet-subject=%22Internal+Medicine%22http://link.springer.com/search?facet-subject=%22Pharmacology%2FToxicology%22http://link.springer.com/search?facet-subject=%22Pharmacotherapy%22http://www.springer.com/journal/40268/submissionhttp://www.springer.com/journal/40268/abouthttp://www.springer.com/journal/40268/edboardhttp://www.springer.com/journal/40268/abouthttp://link.springer.com/journal/40268/7/2/page/1http://link.springer.com/journal/40268http://dx.doi.org/10.1126/science.1090154http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=14615541http://dx.doi.org/10.1038/nm1112


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John G. Houston(1)

Charles F. Albright(1)

Author Affiliations

1. Bristol-Myers Squibb, Pharmaceutical Research Institute, Neuroscience

Drug Discovery, 5 Research Parkway, Wallingford, CT, 06492, USA
http://link.springer.com/search?facet-creator=%22Charles+F.+Albright%22http://link.springer.com/search?facet-creator=%22John+G.+Houston%22

Γ-Secretase Inhibitors for Alzheimer’s Disease - Springer

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