. Common Kibra alleles are associated with human memory performance. Science. 2006 Oct 20;314(5798):475-8. PubMed.


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  1. This paper shows that allelic differences in KIBRA, a protein specifically binding the brain-specific PKC isoform, PKMζ, contribute to variation in human episodic memory performance. This paper follows on the heels of another paper in Science, from our lab, demonstrating that PKMζ is critical for maintaining the hippocampal memory trace in rats for up to one month. The only known function of KIBRA is to bind both PKMζ and the postsynaptic scaffolding protein dendrin; therefore, the new paper suggests that KIBRA is a key player in the localization of PKMζ to synapses. Because mislocalization of PKMζ to the tangles of AD is remarkably specific to tangles in the limbic system (hippocampus, entorhinal cortex, and amygdala) that is essential for episodic memory, and because PKMζ is found only in tangles of people with dementia, and not in the tangles of elderly people without dementia, these new results suggest that the KIBRA-PKMζ pathway is not only an essential pathway for normal memory function, but is the pathway ultimately disrupted in AD that causes loss of memory.


    . Storage of spatial information by the maintenance mechanism of LTP. Science. 2006 Aug 25;313(5790):1141-4. PubMed.

    . Atypical protein kinase C in neurodegenerative disease I: PKMzeta aggregates with limbic neurofibrillary tangles and AMPA receptors in Alzheimer disease. J Neuropathol Exp Neurol. 2006 Apr;65(4):319-26. PubMed.

    View all comments by Todd Sacktor
  2. A recent study by Lauriat and colleagues (1) identifies KIBRA, HAX-1 (antiapoptotic mitochondrial protein) and INTS4 as KIAA0513 interacting proteins.

    INTS4 is part of the integrator complex that directly interacts with the C-terminal domain of the RNA polymerase II largest subunit (2). It has been reported that long-term memory requires de novo RNA synthesis, and I wonder whether a KIBRA/INTS4 association may also underlie its function in enhancing memory. It is interesting that hyperphosphorylation of RNA polymerase II precedes neurofibrillary tangles in AD (3). Casein kinase 2 phosphorylates RNAP II and a recent study finds that ellagic acid is a potent CK2 inhibitor (4). Does the fact that pomegranate juice contains ellagic acid underlie its benefit in reducing amyloid load? (5) It has also been found to inhibit BACE1 (6).

    In his comment, Todd Sacktor suggests that these new results indicate that the KIBRA-PKMζ pathway is not only an essential pathway for normal memory function, but is the pathway ultimately disrupted in AD that causes loss of memory. I also wonder where CAMKII comes into this.

    Hongpaisan and colleagues (7) find calcium entering the mitochondria results in increased O2- production that is essential for the activation of CaMKII. They also report that enhanced O2- production also promoted PKC activity.

    Studies find reduced pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase activity in AD (8) and reduced ability to sequester cytosolic Ca2+ into mitochondria in pyruvate dehydrogenase deficiency (9). Is there a role for reduced mitochondrial Ca2+ and increased SOD1 which may result in reduced CAMKII and PKC activity in the memory deficits in AD and DS?

    Sheline and Mei (10) find that copper facilitated the formation of reactive oxygen species, and inhibited pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. Do you see altered activity of these enzymes with clioquinol treatment?

    Amada and colleagues (11) suggest that N-methyl-D-aspartate receptor deficiency underlies memory impairment in Alzheimer disease, and that this process likely involves insufficient activation of Ca2+/calmodulin-dependent protein kinase II. That may explain the positive reports with the NMDA receptor agonist D-cycloserine. Perhaps the study by Tan (12) may also explain positive results with methylphenidate. He found that CaM-kinase II in the hippocampus and nucleus accumbens of methylphenidate-injected rats had significantly higher calcium-independent activity compared to the controls at 12 weeks old.

    The study by Lindhurst et al. (13) finding that Slc25a19 is a thiamine pyrophosphate transporter is most interesting. Mutations in this gene cause Amish lethal microcephaly. Thiamine pyrophosphate is a cofactor for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. Might reduced activity of these enzymes in DS due to SOD1 overexpression also cause microcephaly? Does reduced activity also release the cofactor and explain the increased serum thiamine pyrophosphate in patients who have DS? Could we expect benefit with thiamine pyrophosphate supplementation?


    . Characterization of KIAA0513, a novel signaling molecule that interacts with modulators of neuroplasticity, apoptosis, and the cytoskeleton. Brain Res. 2006 Nov 22;1121(1):1-11. PubMed.

    . Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II. Cell. 2005 Oct 21;123(2):265-76. PubMed.

    . Hyperphosphorylation of RNA polymerase II and reduced neuronal RNA levels precede neurofibrillary tangles in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Dec;60(12):1219-32. PubMed.

    . Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application. J Med Chem. 2006 Apr 20;49(8):2363-6. PubMed.

    . Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer's disease. Neurobiol Dis. 2006 Dec;24(3):506-15. PubMed.

    . beta-Secretase (BACE1) inhibitors from pomegranate (Punica granatum) husk. Arch Pharm Res. 2005 Dec;28(12):1328-32. PubMed.

    . Strong calcium entry activates mitochondrial superoxide generation, upregulating kinase signaling in hippocampal neurons. J Neurosci. 2004 Dec 1;24(48):10878-87. PubMed.

    . Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol. 2005 May;57(5):695-703. PubMed.

    . Reduced Ca2+ uptake by mitochondria in pyruvate dehydrogenase-deficient human diploid fibroblasts. Am J Physiol. 1998 Mar;274(3 Pt 1):C615-22. PubMed.

    . Free radical-mediated neurotoxicity may be caused by inhibition of mitochondrial dehydrogenases in vitro and in vivo. Neuroscience. 2006 Jun 19;140(1):235-46. PubMed.

    . Reduction of NR1 and phosphorylated Ca2+/calmodulin-dependent protein kinase II levels in Alzheimer's disease. Neuroreport. 2005 Nov 7;16(16):1809-13. PubMed.

    . The activations of calcium/calmodulin-dependent protein kinase II in hippocampus and nucleus accumbens of rats after methylphenidate injection. Kaohsiung J Med Sci. 1999 Oct;15(10):625-31. PubMed.

    . Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia. Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):15927-32. PubMed.

    View all comments by Mary Reid

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