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.

Reference:
Runz H, et al. Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J Neurosci. 1 March 2002;22(5). Abstract