The interesting paper of Rusu and coworkers describes that axonal accumulation of synaptic markers in the fruit fly depends on the NPTY motif of APP. APP overexpression induced a partial but characteristic axonal transport phenotype, which correlated with deficits in short-term synaptic plasticity. This report further supports previous findings in mouse models with mutant or wild-type APP overexpression (1,2), which also elicit aberrant intraneuronal accumulation of Aβ peptides upon reduction of kinesin-I (1). This is an interesting link as intraneuronal Aβ accumulation correlates well with age-dependent axonal degeneration (3,4) and neuron loss of CA1 pyramidal cells (5,6) in two different APP/PS1 mouse lines. It would be interesting to learn whether the NPTY-dependent axonal phenotype in the fruit fly is also based on elevated (intracellular) Aβ accumulation.
1. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease.
Science. 2005 Feb 25;307(5713):1282-8.
2. Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC. Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration.
Neuron. 2006 Jul 6;51(1):29-42.
3. Wirths O, Weis J, Szczygielski J, Multhaup G, Bayer TA. Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer's disease.
Acta Neuropathol (Berl). 2006 Apr;111(4):312-9. Epub 2006 Mar 7.
4. Wirths O, Weis J, Kayed R, Saido TC, Bayer TA. Age-dependent axonal degeneration in an Alzheimer mouse model.
Neurobiol Aging. 2006 Sep 8; [Epub ahead of print]
5. Schmitz C, Rutten BP, Pielen A, Schafer S, Wirths O, Tremp G, Czech C, Blanchard V, Multhaup G, Rezaie P, Korr H, Steinbusch HW, Pradier L, Bayer TA. Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease.
Am J Pathol. 2004 Apr;164(4):1495-502.
6. Casas C, Sergeant N, Itier JM, Blanchard V, Wirths O, van der Kolk N, Vingtdeux V, van de Steeg E, Ret G, Canton T, Drobecq H, Clark A, Bonici B, Delacourte A, Benavides J, Schmitz C, Tremp G, Bayer TA, Benoit P, Pradier L. Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model.
Am J Pathol. 2004 Oct;165(4):1289-300.
View all comments by Thomas Bayer