16 October 2009. The carving up of the amyloid precursor protein (APP) by the successive action of β- and γ-secretases liberates Aβ, but also yields a small intracellular fragment, the APP intracellular domain (AICD). A paper out this week in PNAS from Sanjay Pimplikar’s lab at the Cleveland Clinic, Ohio, provides some in-vivo evidence that AICD is more than just a byproduct of Aβ release, but may have some toxic effects of its own. Pimplikar and colleagues show that transgenic mice overexpressing AICD develop tau pathology, neurodegeneration, and a measurable defect in working memory. The scientists also present evidence that AICD is elevated in brain tissue from AD patients. The results support the idea that some of the pathology now laid on Aβ’s doorstep could instead stem from AICD.
Since its discovery (Passer et al., 2000), AICD has engendered controversy. In 2001, Thomas Sudhof and colleagues, then at University of Texas Southwestern Medical Center in Dallas, showed that after its liberation by the γ-secretase, the AICD enters the nucleus and works together with the nuclear proteins Fe65 and Tip60 to drive transcription of reporter genes (see ARF related news story on Cao and Sudhof, 2001). Pimplikar published similar data (Gao and Pimplikar, 2001). The findings drew a parallel between APP and another γ-secretase substrate, Notch, whose NICD has been implicated in regulation of gene transcription. Since the initial reports, though, there has been little agreement on AICD’s physiological role. No target genes have been definitively identified in vivo for the nuclear complex (e.g., see ARF related news story), and AICD appears to have non-nuclear actions, including disrupting calcium homoeostasis and causing apoptosis.
In the new report, first authors Kaushik Ghosal and Daniel Vogt used an overexpression strategy to probe the potential role of AICD in vivo. In transgenic mice overexpressing both AICD and Fe65, they find phosphorylation and redistribution of tau in young (four-month-old) mice. By eight months, they observe insoluble tau aggregates, and a working memory deficit when animals were tested in a Y maze. After 18 months, the mice showed neuronal loss in the hippocampus. The group had previously shown the mice had abnormal activation of GSK3β (Ryan and Pimplikar, 2005) and here they show that the effects on tau and behavior could be prevented by feeding the animals the GSK3β inhibitor lithium.
The data do not support a role for AICD in gene transcription, however. Previous work showed no evidence of increased mRNA or transcriptional activation of the GSK3β gene in the mice, despite an increase in kinase activity. Possibly, GSK3β is indirectly activated via transcription of other genes, or is subject to post-transcriptional regulation by AICD.
The findings suggest that AICD might contribute to AD pathology independently of Aβ. That raises the question of whether the pathological features seen in AD mouse models arise from AICD, or Aβ, or both. “We have looked at three mouse models so far and we do see increased AICD levels,” Pimplikar told ARF. Because AICD expression seems to be linked to GSK3β activation, Pimplikar says, “As far as tau pathology is concerned, people need to look at AICD as a real strong contender.” In addition, he pointed out another paper just published from the lab showing that the AICD transgenic mice exhibit abnormal neuron spiking and a susceptibility to induced seizures (Vogt et al., 2009), problems that have also been blamed on Aβ production (Palop et al, 2007).
To build more of a case that AICD might be involved in AD, the researchers measured levels of the fragment in human brain samples. When they compared 13 AD patients and 12 non-demented controls, they found the average was significantly higher in patient brain tissue.
The work has many caveats: only one line of transgenic mice was examined, the mice express both AICD and Fe65, and the expression pattern of the transgenes was not compared to pathology. Nonetheless, said Sebastien Hebert, Centre de Recherche du CHUQ, Quebec, Canada, “The effect is there. The work provides strong evidence that overexpression of AICD does cause neurodegeneration. Hopefully the result will be confirmed and a mechanism can be identified.” (Read full comment below from Hebert, who was not involved in the work).
Another result tying AICD to AD comes from Uwe Konietzko and colleagues of the University of Zurich in Switzerland, who report that the nuclear form of AICD is only produced when APP is processed through the amyloidogenic pathway. Processing of APP via the β- or β-secretase pathways can produce AICD, but only fragments derived from endosomal β-secretase cleavage and subsequent γ-secretase processing go on to form a nuclear complex with Fe65 and Tip 60. Processing by α-secretase leads to production of AICD at the plasma membrane, where it is rapidly degraded. That work, published recently in the Journal of Cell Science, places nuclear AICD production specifically on the amyloidogenic pathway of APP processing, and supports the idea that AICD might be elevated in AD along with BACE activity.—Pat McCaffrey.
Ghosal K, Vogt DL, Liang M, Shen Y, Lamb BT, Pimplikar SW. Alzheimer’s disease-like pathological features in transgenic mice expressing the APP intracellular domain. 2009 October 12. PNAS Early Edition. Abstract
Goodger ZV, Rajendran L, Trutzel A, Kohli BM, Nitsch RM, Konietzko U. Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway. J Cell Sci. 2009 Oct 15;122(Pt 20):3703-14. Epub 2009 Sep 22. Abstract