Enzyme BACE1 May Be Important in Predicting Onset of Alzheimer Disease
Elevated BACE1 activity in mild cognitive impairment could be early indicator of Alzheimer Disease, according to new research published in The American Journal of Pathology
Philadelphia, PA, December 12, 2013
The critical enzyme beta-secretase1 (BACE1) is known to
be elevated in brains with sporadic Alzheimer disease (AD). Scientists have now
found increased levels of BACE1 in brains with mild cognitive impairment (MCI),
suggesting that BACE1 activity is important for conversion of mild cognitive
impairment to AD and may be an early indicator of AD. The results are published
in the January issue of The American
Journal of Pathology.
Understanding the early events of AD is key to effective diagnosis and treatment. Two of the major pathological characteristics of AD are neuritic plaques and neurofibrillary tangles, which are used to diagnose or confirm AD at autopsy. Neuritic plaques, which are also known as senile, dendritic, or amyloid plaques, consist of deteriorating neuronal material surrounding deposits of a sticky protein called amyloid beta peptide (Aβ). Neurofibrillary tangles consist of highly phosphorylated forms of the microtubule-associated protein tau.
Following on earlier discoveries that BACE1 activity and protein expression are significantly increased in AD brains, researchers have now found raised levels of BACE1 enzymatic activity in brain tissue from patients with MCI, a precursor to AD. BACE1, also known as β-site amyloid precursor protein cleaving enzyme, is an aspartic protease and is a critical enzyme that promotes Aβ generation.
In the current study, researchers examined autopsied brain tissue from 18 patients with clinically well-characterized AD, 18 patients with MCI, and 18 non-demented patients. They found that BACE1 enzymatic activity was significantly increased in both MCI and AD brains. In 11 of 18 MCI patients, who had undergone a mini-mental state examination (MMSE) before death, the brain cortex BACE1 levels increased during early dementia followed by a precipitous decrease as the decline in cognition progressed. Increased BACE1 activity correlated with plaque numbers and cognition status. Interestingly, they also observed that there was no significant difference in BACE1 activity between MCI and AD.
The researchers also found an increase in tumor necrosis factor alpha (TNFα) in MCI brains. TNFα is an inflammatory cytokine or cell signaling protein required for amyloid protein induced neuronal death. Biochemical examination of the autopsy tissue showed that TNFα rather than other cytokines increases the response to BACE1 protein expression. The increased levels of TNFα in MCI and AD patients were not significantly different from each other.
"There is more and more evidence that BACE1 is intricately involved in the development of AD," says the study's lead investigator Yong Shen, PhD, of the Center for Advanced Therapeutic Strategies for Brain Disorders at Roskamp Institute, Sarasota, Florida. "Our previous studies have demonstrated elevated BACE1 enzymatic activity in AD brains and in the cerebrospinal fluid from MCI and AD patients. Our findings here suggest that BACE1 increases early in the course of MCI and is possibly induced by inflammatory molecules like TNFα and that BACE1 enzymatic activity may be important for conversion of MCI to AD. Importantly, we found that the BACE1 activity in tissue from people with MCI was significantly increased by 27%, compared with that from people with no dementia.
"We believe that BACE1 activity precedes the clinical diagnosis of AD and could be an early indicator of neuronal dysfunction or pathology in AD. Moreover, it may be a good therapeutic target for AD, as evidenced by recent promising clinical trials on BACE1 inhibitors," he concludes.
# # #
Notes for editors
"High Activities of BACE1 in Brains with Mild Cognitive Impairment," by Xin Cheng, Ping He, Taehee Lee, Hailan Yao, Rena Li, Yong Shen (DOI: http://dx.doi.org/10.1016/j.ajpath.2013.10.002), The American Journal of Pathology, Volume 184, Issue 1 (January 2014) published by Elsevier.
Full text of the article is available to credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or firstname.lastname@example.org. Journalists wishing to interview the authors should contact Dr. Yong Shen at +1 941 752 2949 or email@example.com.
This work was supported by grants from NIH/NIA025888 (YS), NIH/NIAR01AG032441 (RL), Alzheimer Association: IIRG-09-61521 (YS) and IIRG-07-59510 (RL); AHAF: G2006-118 (RL); A2008-642 (PH), and National Natural Science Foundation of China 81100861 (XC), and Specialized Research Fund for the Doctoral Program of Higher Education 20100071120081 (XC).
About The American Journal of Pathology
The American Journal of Pathology (http://ajp.amjpathol.org), official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.
The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – over 38,000 citations in 2012 – with an Impact Factor of 4.522 and Eigenfactor of 0.07599 according to the 2012 Journal Citation Reports®, Thomson Reuters, and an h-index of 181 according to the 2011 SCImago Journal and Country Rank.
Elsevier is a global information analytics business that helps institutions and professionals progress science, advance healthcare and improve performance for the benefit of humanity. Elsevier provides digital solutions and tools in the areas of strategic research management, R&D performance, clinical decision support, and professional education; including ScienceDirect, Scopus, SciVal, ClinicalKey and Sherpath. Elsevier publishes over 2,500 digitized journals, including The Lancet and Cell, more than 35,000 e-book titles and many iconic reference works, including Gray's Anatomy. Elsevier is part of RELX Group, a global provider of information and analytics for professionals and business customers across industries. www.elsevier.com