Year: 2008
Type: article
Abstract: The phosphotyrosine binding (PTB) domain of the neuronal adaptor protein X11alpha/mint-1/APBA-1 binds to the conserved -YENPTY- motif in the cytoplasmic domain of amyloid precursor protein (APP) to modulate its metabolism. While the effects of X11alpha overexpression have been studied in vitro and in vivo, the effects of X11alpha depletion on hAPPswe metabolism have not been examined in neuronal cultures or in vivo. To probe the effects of X11alpha depletion on hAPPswe metabolism we crossed hAPPswe/hPS-1delE9 transgenic mice with X11alpha-deficient (+/-) mice--all in the C57BL/6J background. Mouse genotypes were determined by PCR of gDNA. Embryonal (E16) neuronal cultures were generated from the cerebral cortex of hAPPswe/hPS-1delE9 versus hAPPswe/hPS-1delE9/X11alpha-deficient pups. Levels of Abeta40 and Abeta42 were measured in conditioned media by sandwich ELISA after eight days in vitro, and in brain homogenates of 12-month old mice. Amyloid plaque densities were determined by stereologic counts of silver-stained brain sections. Immunoblot of proteins extracted from brain homogenates of X11alpha-deficient (+/-) mice confirmed a reduced level of expression compared to wt (+/+) mice. Compared to conditioned media from hAPPswe/hPS-1delE9 neuronal cultures, media derived from hAPPswe/hPS-1delE9/X11alpha-deficient mice contained significantly less Abeta40. However, the levels of Abeta40 and Abeta42, and the APP C-terminal fragments C99 and C83 were all significantly increased in brain homogenates of 12-month old hAPPswe/hPS-1delE9/X11alpha-deficient mice. The amyloid plaque burden in hippocampus was significantly increased in hAPPswe/PS-1delE9/X11alpha-deficient mice versus hAPPswe/PS-1delE9 mice. These data suggest a regulatory role for X11alpha on the gamma-cleavage of C99 and C83, and a regulatory role for X11alpha on APPswe catabolism in vivo.
Source: Alzheimer s & Dementia
Authors: Inderjeet Saluja, Raymond S. Turner
Institution: University of Michigan
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1973490290