Cortico-Cortical Connectivity: A Key Aspect to Neurodegeneration
The work from William Yang and colleagues (Gu et al., 2005), while directed toward Huntington’s disease (HD), is likely broadly applicable to a number of neurodegenerative disorders including Alzheimer disease (AD). Using two different Cre/LoxP conditional mouse models of HD, these investigators show that restricting mutant huntingtin (mhtt) expression to cortical pyramidal neurons, while capable of forming intracellular aggregates, had no effect on neuropathological hallmarks (reactive gliosis, dysmorphic neuritis, and dark neuron degeneration) nor elicited motor deficits. By marked contrast, expression of mhtt in all of the neurons of the brain resulted in the full spectrum of pathological and motor changes associated with HD. While the issue of whether mhtt expression in pyramidal neurons is necessary for toxicity was not addressed, the overall conclusion that pathological cell-cell interactions are significant contributors to neuronal toxicity in vivo is supported by this and other studies in human...  Read more

Cortico-Cortical Connectivity: A Key Aspect to Neurodegeneration
The work from William Yang and colleagues (Gu et al., 2005), while directed toward Huntington’s disease (HD), is likely broadly applicable to a number of neurodegenerative disorders including Alzheimer disease (AD). Using two different Cre/LoxP conditional mouse models of HD, these investigators show that restricting mutant huntingtin (mhtt) expression to cortical pyramidal neurons, while capable of forming intracellular aggregates, had no effect on neuropathological hallmarks (reactive gliosis, dysmorphic neuritis, and dark neuron degeneration) nor elicited motor deficits. By marked contrast, expression of mhtt in all of the neurons of the brain resulted in the full spectrum of pathological and motor changes associated with HD. While the issue of whether mhtt expression in pyramidal neurons is necessary for toxicity was not addressed, the overall conclusion that pathological cell-cell interactions are significant contributors to neuronal toxicity in vivo is supported by this and other studies in human (Ferrer et al., 1994) and mouse models (Kosinski et al., 1999). The implications of this study go far beyond HD and are likely significant in a number of brain disorders. Indeed, aberrations in cortical circuitry are also thought to play a significant role in the pathogenesis of AD (De Lacoste and White, 1993) and provide an explanation not only for the regional selectivity of the disease, but also the progressive nature and pattern of the disease. As such, and in light of the current findings showing that expression of mhtt in a single neuronal population was insufficient to cause disease (Gu et al., 2005), the culprit in AD may operate at some distance from the scene of the crime. The question as to whether this makes juxtaposed elements, such as phospho-tau and intracellular amyloid aggregates, accomplices or innocent bystanders (Rottkamp et al., 2002; Lee et al., 2005) is key to understand before we leave the crime scene and cast our nets further afield. Gemma Casadesus, Mark A. Smith and George Perry

References:
De Lacoste, M.C. and White, C. L. 3rd. (1993) The role of cortical connectivity in Alzheimer's disease pathogenesis: a review ad model system. Neurobiol. Aging, 14, 1-16. Abstract

Ferrer, I., Kulisevsky, J., Gonzalez, G., Escartin, A., Chivite, A., and Casas, R. (1994). Parvalbumin-immunoreactive neurons in the cerebral cortex and striatum in Huntington’s disease. Neurodegeneration, 3, 169–173.

Gu, X., Li, C., Wei, W., Lo, V., Gong, S., Li, S.-H., Iwasato, T., Itohara, S., Li, X.-J., and Yang, X.W. (2005) Pathological cell-cell interactions elicited by a neuropathogenic form of mutant huntingtin contribute to cortical pathogenesis in HD mice. Neuron, 46, 433-444. Abstract

Kosinski, C.M., Cha, J.H., Young, A.B., Mangiarini, L., Bates, G., Schiefer, J., and Schwarz, M. (1999). Intranuclear inclusions in sub-types of striatal neurons in Huntington’s disease transgenic mice. Neuroreport, 10, 3891–3896. Abstract Lee, H.G., Perry, G., Moreira, P.I., Garrett, M.R., Liu, Q., Zhu, X., Takeda, A., Nunomura, A. and Smith, M.A. (2005) Tau phosphorylation in Alzheimer's disease: pathogen or protector? Trends Mol Med., 11, 164-9. Abstract Rottkamp, C.A., Atwood, C.S., Joseph, J.A., Nunomura, A., Perry, G., and Smith, M.A. (2002) The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease. Peptides, 23, 1333-41. Abstract

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