I really like this paper and think it is quite important. However, some caution should be given to the interpretation of "membrane-associated" IDE. In our experience, most membrane purification protocols actually end up purifying largely mitochondrial IDE, a pool that is generated from alternative translation initiation (Leissring et al., 2004). In fact, rigorous washing with bicarbonate and sonication removes all of the IDE in the "membrane fraction," suggesting that the IDE is actually in the inner matrix of the mitochondrion (see Farris et al., 2005).

Nonetheless, this finding may be of high significance itself, if mitochondrial IDE actually plays some protective role in AD, a hypothesis we are currently investigating. Also, it is very likely that the levels of mitochondrial IDE track with cytosolic and other pools of IDE.

References:
Farris W, Leissring MA, Hemming ML, Chang AY, Selkoe DJ. Alternative splicing of human insulin-degrading enzyme yields a novel isoform with a decreased ability to degrade insulin and amyloid beta-protein. Biochemistry. 2005 May 3;44(17):6513-25. Abstract

Leissring MA, Farris W, Wu X, Christodoulou DC, Haigis MC, Guarente L, Selkoe DJ. Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria. Biochem J. 2004 Nov 1;383(Pt. 3):439-46. Abstract

View all comments by Malcolm Leissring

This elegant voxel-based morphometric study demonstrates white matter degeneration of the anteromedial parahippocampal gyrus. The authors have attributed these changes, at least in part, to degeneration of the perforant pathway connecting the entorhinal cortex to the CA1 and dentate gyrus of the hippocampus. Consistent with these findings, our group recently demonstrated preferential atrophy of the CA1 in amnestic mild cognitive impairment patients who progress to Alzheimer disease.

References:
Apostolova LG, Dutton RA, Dinov ID, Hayashi KM, Toga AW, Cummings JL, Thompson PM. Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps. Arch Neurol. 2006 May;63(5):693-9. Abstract

View all comments by Liana Apostolova

Neuronal Loss Specific to Hippocampus in AD
Regional specificity of neuronal loss in Alzheimer disease was a long observed but unexplained topic, wherein many explanations have been put forward in the recent past. The recent report of Zhao et al., 2006, is an excellent attempt to explain why there is a hippocampal-specific neurodegeneration-related change (e.g., the B to Z transition in the DNA conformation) in the hippocampus of moderately and severely affected Alzheimer disease patients. Earlier, Sugaya et al., 1997, reported the topographic association between DNA fragmentation in the hippocampus and Alzheimer disease neuropathology. Zhao et al., 2006, seem to prove that decreased IDE level in hippocampus is related to progressive clinical dementia, but how neuronal abnormalities specific to the hippocampus lead to detectable alteration in IDE is still not clear.

References:
Suram A, Jagannatha K.S., Latha K.S. and Viswamitra M.A. First evidence to show the topological change of DNA from B-DNA to Z-DNA conformation in the hippocampus of Alzheimer’s brain. J. Neuromolecular. Med. (2002) 2: 287-295.

Sugaya K., Reeves M. and McKinney M. Topographic associations between DNA fragmentation and Alzheimer’s disease neuropathology in the hippocampus. Neurochem. Int. (1997) 31: 275-281. Abstract

View all comments by Veer Bala Gupta
View all comments by K.S. Jagannatha Rao