Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo.

Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo. Research Abstract Details 

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Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo. Abstract Text:

Sam Gandy,Yun-wu Zhang,Annat Ikin,Stephen D Schmidt,Alexey Bogush,Efrat Levy,Roxanne Sheffield,Ralph A Nixon,Francesca-Fang Liao,Paul M Mathews,Huaxi Xu,Michelle E Ehrlich,

Studies in continuously cultured cells have established that familial Alzheimer's disease (FAD) mutant presenilin 1 (PS1) delays exit of the amyloid precursor protein (APP) from the trans-Golgi network (TGN). Here we report the first description of PS1-regulated APP trafficking in cerebral neurons in culture and in vivo. Using neurons from transgenic mice or a cell-free APP transport vesicle biogenesis system derived from the TGN of those neurons, we demonstrated that knocking-in an FAD-associated mutant PS1 transgene was associated with delayed kinetics of APP arrival at the cell surface. Apparently, this delay was at least partially attributable to impaired exit of APP from the TGN, which was documented in the cell-free APP transport vesicle biogenesis assay. To extend the study to APP and carboxyl terminal fragment (CTF) trafficking to cerebral neurons in vivo, we performed subcellular fractionation of brains from APP transgenic mice, some of which carried a second transgene encoding an FAD-associated mutant form of PS1. The presence of the FAD mutant PS1 was associated with a slight shift in the subcellular localization of both holoAPP and APP CTFs toward iodixanol density gradient fractions that were enriched in a marker for the TGN. In a parallel set of experiments, we used an APP : furin chimeric protein strategy to test the effect of artificially forcing TGN concentration of an APP : furin chimera that could be a substrate for beta- and gamma-cleavage. This chimeric substrate generated excess Abeta42 when compared with wildtype APP. These data indicate that the presence of an FAD-associated mutant human PS1 transgene is associated with redistribution of the APP and APP CTFs in brain neurons toward TGN-enriched fractions. The chimera experiment suggests that TGN-enrichment of a beta-/gamma-secretase substrate may play an integral role in the action of mutant PS1 to elevate brain levels of Abeta42.

Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo. Publishing Authors By Initials

S Gandy,YW Zhang,A Ikin,SD Schmidt,A Bogush,E Levy,R Sheffield,RA Nixon,FF Liao,PM Mathews,H Xu,ME Ehrlich,

For similar cells: cellular structures: intracellular space: cytoplasm: cytoplasmic structures: organelles: golgi apparatus: trans-golgi network research abstracts see: cells: cellular structures: intracellular space: cytoplasm: cytoplasmic structures: organelles: golgi apparatus: trans-golgi network research

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Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Journal of neurochemistry

VOLUME: 102

Page Numbers: 619-26

Journal Abbreviation: J. Neurochem.

ISSN: 0022-3042

DAY: 3

MONTH: Aug

YEAR: 2007

Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985190

Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo. Keywords Mesh Terms:

KEYWORDS: trans-Golgi Network

MESH TERMS: metabolism

Chemical & Substance for Abstract: Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo. Information

Substance Name: Flavin-Adenine Dinucleotide

Registry Number: 146-14-5

Grant and Affiliation Information for Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo.

AFFILIATION: Farber Institute for Neurosciences and the Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. samgandy@earthlink.net

Country: England

AGENCY: United States NINDS

GRANT: NS46673

ACRONYM: NS

MEDLINETA: J Neurochem

REFSOURCE: J Neurochem. 2007 Nov;103(3):1272

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