A provocative paper providing new insights into the onset of Abeta amyloidosis in FAD. It also raises intriguing questions as to whether or not FAD and sporadic AD and Down syndrome evolve in the same locations and same manner. It also raises question about we are how to understand the disconnection between striatal Abeta deposits and the lack of clinical symptoms, signficant neuron loss, and tau pathology linked to striatal accumulations of Abeta deposits.

View all comments by John Trojanowski

These findings suggest more a loss of function of APP/AICD than a gain of toxic function, since there is no correlation between the precise early distribution of amyloid and clinical impairment.

View all comments by Andre Delacourte

The work by Klunk and coworkers (2007) demonstrates how incomplete our understanding is of the early neuropathobiological events that occur in both FAD as well as sporadic AD. Interestingly, we recently demonstrated an age-related increase in striatal amyloid-containing plaques associated with neuritic pathology in APPswe/PS1δE9 mice (Perez et al., 2005). Whether striatal plaque pathology is a very early event compared to cortical and hippocampal pathology in these mice remains an unanswered question. If so, then this mutant may be a putative animal model for both AD and FAD as well as the investigation of early treatment strategies.

References:
Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Hoge JA, Cohen AD, Ikonomovic MD, Saxton JA, Snitz BE, Pollen DA, Moonis M, Lippa CF, Swearer JM, Johnson KA, Rentz DM, Fischman AJ, Aizenstein HJ, DeKosky ST. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. Abstract

Perez SE, Lazarov O, Koprich J.B, Chen E-Y, Rodriguez V, Lipton JW, Sisodia SS, Mufson EJ. Nigrostriatal dysfunction in FAD-linked APPswe/PS1Delta E9 transgenic mice. J. Neurosci. 2005;25: 10220-10229. Abstract

View all comments by Elliott Mufson

This is the first paper to show (11)C-PiB binding in PET in hereditary cerebral amyloid angiopathy and APP locus duplication. The paper reports increased uptake of (11)C-PiB in the striatum and the posterior cingulate in two cases with APP duplication, while there was only a marginal increase in cortical regions. The finding suggests that PIB-PET may be useful in investigating subjects with suspected CAA.

View all comments by Hilkka Soininen