Abstract Details

Title Is There Functional Redundancy between APP and APLP2?

Topic Aging and Dementia

Presentation(s) (-)

Poster/Presentation
Number 010

Objective

Background The amyloid cascade hypothesis implies that down-regulating APP translation would delay or prevent Alzheimer's disease. Yet the role(s) of APP is/are not well understood, and its disruption may be deleterious. The APP homologue APLP2 does not contain the A? sequence, but may display functional redundancy with APP, allowing safe down-regulation of the latter.

Design/Methods APP and APLP2 transcript and protein levels in cortex and cerebellum of WT, APP KO (-/-) or APLP2 KO (-/-) mice were determined by rtPCR and Western blotting, respectively. Neurite outgrowth was assessed by timelapse DIC videomicroscopy of primary (E14) neuronal cultures from APP, APLP2, and double KO mice, compared with WT. In a further series of experiments, fluorescently-tagged siRNA's were used to knock down APP in established (day 4) primary neuronal cultures, and then neurons identified as transfected were subject to time lapse microscopy between days 5 and 6.

Results APP KO (-/-) mice showed up-regulation of APLP2 protein but not transcript levels, but only in cortex and only at postnatal day 2, while APP was not up-regulated in APLP2 KO mice. APP KO or APP/APLP2 double KO primary neurons showed decreased neurite extension compared with APLP2 KO or WT neurons. siRNA knock-down of APP from days 4-6 in vitro also impaired neurite outgrowth.

Conclusions There is insufficient functional redundancy between APP and APLP2 for APLP2 to mitigate the effects of APP down-regulation on neurite outgrowth. This suggests that APP down-regulation as a therapeutic approach may possibly have deleterious effects on, for example, neurogenesis in the adult hippocampus.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
Claudia A. Chiriboga, MD, FAAN (Columbia University)	Dr. Chiriboga has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentec. Dr. Chiriboga has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. The institution of Dr. Chiriboga has received research support from Roche. The institution of Dr. Chiriboga has received research support from Avexis/Novartis. The institution of Dr. Chiriboga has received research support from Biogen. The institution of Dr. Chiriboga has received research support from NIH. The institution of Dr. Chiriboga has received research support from Biohaven. The institution of Dr. Chiriboga has received research support from Genentec. Dr. Chiriboga has received publishing royalties from a publication relating to health care.
Elsdon Storey, FRACP, DPhil (Monash University, ASPREE, SPHPM)	No disclosure on file
Christiana E. Hall, MD (UT Southwestern)	No disclosure on file

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