Raymond T Bartus1, Reginald L Dean. 1. Ceregene, Inc., 9381 Judicial Dr., Suite 130, San Diego, CA 92121, USA. rtbartus@ceregene.com
Abstract
RATIONALE: Over 30 years ago, we began to develop a nonhuman primate model to study cognitive deficits of age-related neurodegenerative diseases and their neuroanatomical-neurochemical underpinnings for purposes of translating this work toward first pharmacotherapies. This effort produced several notable findings that eventually received consensus support, which we have been asked to review. OBJECTIVES: A discussion of these findings, in the context of issues and obstacles confronted and principles applied, might facilitate the development of even more effective models and treatments, not only for Alzheimer's disease (AD) but for many other disorders involving cognitive deficits. RESULTS: Collectively, our research provided first evidence of the following: aged primates can be used as 'models' for human age-related neurodegenerative diseases; key cognitive deficits in early AD share important conceptual similarities to deficits in both aged monkeys as well as non-demented humans (e.g., age-associated memory impairment and mild cognitive impairment); pharmacological intervention can reduce age-related cognitive impairments in animals that are conceptually similar to those seen in human diseases, including AD; cholinergics would likely be the first approved therapeutics for AD; and that many other classes of drugs would not likely succeed. CONCLUSIONS: Despite the early promise shown by behavioral/functional approaches to develop treatment strategies, the dramatic shift in focus away from behavioral outcomes in animal neurodegenerative research that began 20 years ago has compromised further progress and continues to impede our ability to understand how these diseases impair human cognition and what pathways might lead to effective therapies. Principles applied successfully in the past should provide guidance for facilitating efforts in the future.
RATIONALE: Over 30 years ago, we began to develop a nonhuman primate model to study cognitive deficits of age-related neurodegenerative diseases and their neuroanatomical-neurochemical underpinnings for purposes of translating this work toward first pharmacotherapies. This effort produced several notable findings that eventually received consensus support, which we have been asked to review. OBJECTIVES: A discussion of these findings, in the context of issues and obstacles confronted and principles applied, might facilitate the development of even more effective models and treatments, not only for Alzheimer's disease (AD) but for many other disorders involving cognitive deficits. RESULTS: Collectively, our research provided first evidence of the following: aged primates can be used as 'models' for human age-related neurodegenerative diseases; key cognitive deficits in early AD share important conceptual similarities to deficits in both aged monkeys as well as non-demented humans (e.g., age-associated memory impairment and mild cognitive impairment); pharmacological intervention can reduce age-related cognitive impairments in animals that are conceptually similar to those seen in human diseases, including AD; cholinergics would likely be the first approved therapeutics for AD; and that many other classes of drugs would not likely succeed. CONCLUSIONS: Despite the early promise shown by behavioral/functional approaches to develop treatment strategies, the dramatic shift in focus away from behavioral outcomes in animal neurodegenerative research that began 20 years ago has compromised further progress and continues to impede our ability to understand how these diseases impair human cognition and what pathways might lead to effective therapies. Principles applied successfully in the past should provide guidance for facilitating efforts in the future.
Authors: M Eriksdotter Jönhagen; A Nordberg; K Amberla; L Bäckman; T Ebendal; B Meyerson; L Olson; M Shigeta; E Theodorsson; M Viitanen; B Winblad; L O Wahlund Journal: Dement Geriatr Cogn Disord Date: 1998 Sep-Oct Impact factor: 2.959
Authors: Christopher D Herzog; Kathie M Bishop; Lamar Brown; Alistair Wilson; Jeffrey H Kordower; Raymond T Bartus Journal: Drug Deliv Transl Res Date: 2011-10 Impact factor: 4.617
Authors: Rui Liu; Cai-Xia Wu; Dan Zhou; Fan Yang; Shuo Tian; Li Zhang; Tian-Tai Zhang; Guan-Hua Du Journal: BMC Med Date: 2012-09-18 Impact factor: 8.775