In the earliest stages of Alzheimer disease, Aβ is on the rise, especially in the hippocampus and entorhinal cortex, two connected brain regions critical for memory. Now, Giulio Maria Pasinetti and coworkers at the Mount Sinai School of Medicine in New York suggest one reason for that early increase: a slowing of the breakdown of Aβ peptides by the insulin-degrading enzyme (IDE). In a paper published online June 10 in the journal Neurobiology of Aging, the researchers show that the membrane-bound form of IDE is selectively decreased in the hippocampus of people with mild cognitive impairment (MCI). They also show a further decline in IDE protein and activity with the progression to AD, which correlates with the increase in Aβx-42 peptides in the entorhinal cortex.

A loss of IDE activity has been previously shown to occur with aging and in severe AD (Cook et al., 2003; Farris et al., 2004), and the current results raise the possibility that a deficit in degradation could raise levels of the toxic Aβ peptide early in AD. If these results are confirmed, they suggest that boosting IDE activity could reverse Aβ accumulation, and may provide a therapeutic angle to preventing dementia.

Keeping the focus on early changes, a new imaging study from Raj Shah and colleagues at Rush University in Chicago reveals changes not just in the grey matter of the hippocampus and entorhinal cortex in MCI, but also in the white matter that connects them. Their results show that loss of white matter volume in the parahippocampal gyrus contributes to the memory decline, possibly by disconnecting the hippocampus from sensory inputs.

But first, the IDE story. To assess possible changes in IDE during MCI, first author Zhong Zhao and colleagues measured protein levels and enzymatic activity in fresh postmortem brain tissue from 46 elderly subjects. All the subjects had been evaluated during the previous 6 months and assigned a clinical dementia rating score (CDR) between 0 (normal cognition) and 5 (severe dementia). When the researchers measured IDE by Western blotting, they found that hippocampal membrane-bound IDE (the type mostly associated with neurons) was decreased significantly in the CDR = 0.5 (MCI) group. Protein levels were further decreased in patients with increasing CDR scores. As assessed by insulin degradation, the membrane-bound hippocampal IDE activity was reduced about 20 percent in the MCI group, with a further additional 10 percent decline in brains from patients with advanced AD. For cytosolic IDE, which may be mostly derived from microglia, the authors detected some evidence of decline, but the changes were not statistically significant. The loss of IDE activity was most pronounced in the hippocampus: though some declines were seen in lysates from the occipital cortex, the changes were not statistically significant.

The researchers also measured levels of Aβ peptides in the entorhinal cortex and found that the amount of Aβx-42 was inversely correlated with membrane-bound IDE activity they measured in the hippocampus. These results support the idea that alterations in IDE might be causally related to Aβ accumulation, starting in the earliest stages of AD. The authors conclude cautiously, “Our phenomenological study for the time tentatively suggests that interventions aimed at promoting IDE activities in the brain in MCI might beneficially delay the onset of AD dementia through mechanisms that promote clearance of amyloidogenic monomeric Aβ peptides from the brain.”

Perhaps as a result of the early assault by Aβ, MRI scans show atrophy and loss of volume in the hippocampus and entorhinal cortex that correlate with memory loss in MCI patients. In the imaging study, first author Travis Stoub and coworkers uncovered an additional problem in this region. By focusing on white matter changes in MCI patients, they found atrophy in the parahippocampal gyrus, which includes the perforant path linking the entorhinal cortex and the hippocampus. In quantitative, high resolution brainwide scans, this area was the only place where they detected white matter decreases in a large cohort of MCI patients (n = 40) compared to normal individuals (n = 50).

Statistical analysis showed that decrease in any of the three areas (white matter of the parahippocampus, or grey matter of the hippocampus or entorhinal cortex) predicted the extent of memory decline. When all three regions were analyzed simultaneously, only the changes in hippocampal and white matter volume were significantly predictive of memory function. From this, the authors conclude that disruption of the parahippocampal white matter fibers make a significant contribution, along with hippocampal atrophy, to the memory deficits seen in MCI, possibly by causing a partial disconnection of the hippocampus from sensory information coming in via the entorhinal cortex. As they point out, the imaging data bears out the very hypothesis first proposed by Brad Hyman and colleagues more than 20 years ago, based on postmortem neuroanatomical investigations (Hyman et al., 1984).—Pat McCaffrey.

Reference:
Zhao Z, Xiang Z, Haroutunian V, Buxbaum J, Stetka B, Pasinetti GM. Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease. Neurobiol Aging. 2006 Jun 10; [Epub ahead of print] Abstract

Stoub TR, deToledo-Morrell L, Stebbins GT, Leurgans S, Bennett DA, Shah RJ. Hippocampal disconnection contributes to memory dysfunction in individuals at risk of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):10041-10045. Epub 2006 Jun 19. Abstract

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  1. The authors demonstrate a potential role of IDE, direct or indirect, in Abeta metabolism. It is however hard to understand why other proteases involved in Abeta metabolism such as BACE-1, neprilysin, or ECE was not quantified using the same samples. I also recommend Zhao et al. eximine the quantity of AICD because AICD is a far better substrate for IDE than any other protein thus far reported.

    View all comments by Takaomi Saido
  2. 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:

    . 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. PubMed.

    . Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria. Biochem J. 2004 Nov 1;383(Pt. 3):439-46. PubMed.

  3. 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:

    . Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps. Arch Neurol. 2006 May;63(5):693-9. PubMed.

  4. 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:

    . First evidence to show the topological change of DNA from B-dNA to Z-DNA conformation in the hippocampus of Alzheimer's brain. Neuromolecular Med. 2002;2(3):289-97. PubMed.

    . Topographic associations between DNA fragmentation and Alzheimer's disease neuropathology in the hippocampus. Neurochem Int. 1997 Aug;31(2):275-81. PubMed.

References

Paper Citations

  1. . Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol. 2003 Jan;162(1):313-9. PubMed.
  2. . Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol. 2004 Apr;164(4):1425-34. PubMed.
  3. . Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science. 1984 Sep 14;225(4667):1168-70. PubMed.
  4. . Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease. Neurobiol Aging. 2007 Jun;28(6):824-30. PubMed.
  5. . Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):10041-5. PubMed.

Further Reading

Papers

  1. . Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease. Neurobiol Aging. 2007 Jun;28(6):824-30. PubMed.
  2. . Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):10041-5. PubMed.

Primary Papers

  1. . Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease. Neurobiol Aging. 2007 Jun;28(6):824-30. PubMed.
  2. . Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):10041-5. PubMed.