An article in tomorrow's Journal of Neuroscience adds a few clues to the still-murky relationship between cholesterol and Alzheimer disease. Researchers puzzle over cholesterol's role in AD in part because they don't understand well enough the basic biology of the different cellular compartments (the cell membrane, endoplasmic reticulum [ER], Golgi complex) that sort and sequester, alter and transport, degrade or release a multitude of complex molecules, including the main suspects in AD. (See related ARF news item.)
Tobias Hartmann , Heiko Runz, and colleagues at the University of Heidelberg and the European Molecular Biology Laboratory in Heidelberg, Germany, and elsewhere, focused on a small part of the far-flung intracellular cholesterol picture, namely the pathway that takes the steroid from sorting vesicles called late endosomes into the ER. They exploited two different methods of manipulating this transport: The use of compounds that inhibit cholesterol transport, and assays in cells with a protein mutation that traps cholesterol inside late endosomes.
In both cases, they found an interesting inverse effect on β- and γ-secretase, the two enzymes required for production of the toxic forms of Aβ. β-Secretase cleavage of amyloid precursor protein (AβPP) was markedly decreased, whereas γ-secretase cleavage was increased, yielding more Aβ. In addition, the researchers were surprised to find the presenilins (PS1 and PS2) accumulating in vesicular (Rab7-positive) compartments adjacent to the late endosomes that were accumulating cholesterol. "Because Aβ 1-42 also localized to PS1-containing vesicular compartments, organelles involved in cholesterol transport might represent an important site for γ-secretase activity," they write. If this were true, it would help resolve a long-standing debate.—Hakon Heimer
- Runz H, Rietdorf J, Tomic I, de Bernard M, Beyreuther K, Pepperkok R, Hartmann T. Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J Neurosci. 2002 Mar 1;22(5):1679-89. PubMed.