Amyloid-β Production Via Cleavage of Amyloid-β Protein Precursor is Modulated by Cell Density

Article type: Research Article

Authors: Zhang, Can^a | Browne, Andrew^a | DiVito, Jason R.^a | Stevenson, Jesse A.^a | Romano, Donna^a | Dong, Yuanlin^{a; b} | Xie, Zhongcong^{a; b} | Tanzi, Rudolph E.^{a; *}

Affiliations: [a] Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA | [b] Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

Correspondence: [*] Correspondence to: Rudolph E. Tanzi, Ph.D., Joseph P. and Rose F. Kennedy Professor of Neurology, Harvard Medical School, Director, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA. Tel.: +1 617 726 6845; Fax: +1 617 724 1949; E-mail: tanzi@helix.mgh.harvard.edu.

Note: [] Handling Associate Editor: Debomoy Lahiri

Abstract: Mounting evidence suggests that Alzheimer's disease (AD) is caused by the accumulation of the small peptide, amyloid-β (Aβ), a proteolytic cleavage product of amyloid-β protein precursor (AβPP). Aβ is generated through a serial cleavage of AβPP by β- and γ-secretase. Aβ40 and Aβ42 are the two main components of amyloid plaques in AD brains, with Aβ42 being more prone to aggregation. AβPP can also be processed by α-secretase, which cleaves AβPP within the Aβ sequence, thereby preventing the generation of Aβ. Little is currently known regarding the effects of cell density on AβPP processing and Aβ generation. Here we assessed the effects of cell density on AβPP processing in neuronal and non-neuronal cell lines, as well as mouse primary cortical neurons. We found that decreased cell density significantly increases levels of Aβ40, Aβ42, total Aβ, and the ratio of Aβ42: Aβ40. These results also indicate that cell density is a significant modulator of AβPP processing. Overall, these findings carry profound implications for both previous and forthcoming studies aiming to assess the effects of various conditions and genetic/chemical factors, e.g., novel drugs on AβPP processing and Aβ generation in cell-based systems. Moreover, it is interesting to speculate whether cell density changes in vivo may also affect AβPP processing and Aβ levels in the AD brain.

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, cell density

DOI: 10.3233/JAD-2010-100816

Journal: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 683-694, 2010