NCAMs in the HD mice

Marsha L. Miller, Ph.D., Mar, 02/06/2007

Problems with neural cell adhesion molecules may explain cognitive and olfactory dysfunction in HD. CHDI is funding preclinical testing with a NCAM mimetic.
This very interesting article identifies a new pathology in two HD mouse models which may explain early cognitive problems and impairment of the sense of smell.

NCAMs are neural cell adhesion molecules. When they are modified by polysialic acid, they are associated with brain plasticity, or the ability of the brain to reorganize neural pathways as a result of learning and new experiences. Obviously the greatest period of brain plasticity occurs during the developmental years, but changes occur throughout the life span as we acquire new information and skills. Plasticity also occurs in response to injury as the brain attempts to adapt.

The researchers reasoned that since cognitive and olfactory impairments are present early in HD, it would be a good idea to take a closer look at the specific areas of the hippocampus and cortex which are involved with both of these functions. They found that the number of neurons expressing polysialylated neural cell adhesion molecules was reduced in both the dentate gyrus of the hippocampus and in layer II of the piriform cortex of mouse models R6/1 and R6/2.

Given the methodology of the study, they could not tell whether this reduction was caused by an overall reduction in NCAMs or whether it was a decrease in polysialylation. In any case, this looks like an important pathology and one which could be a target for drug development.

Neural cell adhesion molecules are fascinating things that I didn't know anything about until just last year. They act as fibroblast growth factor receptor agonists and therefore are part of the the neuroprotection process associated with growth factors. They also allow neurons to connect to each other and play an important role in the development and migration of neurons as well as in the formation and consolidation of memory. A primary different between humans and primates is that we have more genes that relate to NCAMs.

CHDI is already funding the preclinical testing for a NCAM mimetic which clearly shows how much they are on the cutting edge of drug development and testing. It is very encouraging to see that as major new findings with therapeutic implications emerge about Huntington's Disease -- the NCAM, caspase 6 and the molecular 'zip codes,' CHDI is ready with funding. See: http://www.hdlighthouse.org/research/drugs-supps/updates/1344chdi.php

Marsha L. Miller, Ph.D.
Karin Van der Borght, Ph.D., Neuronal Survival Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Sweden
Reduced expression of PSA-NCAM in the hippocampus and piriform cortex of the R6/1 and R6/2 mouse models of Huntington's disease
Karin van der Borght and Patrik Brundin
Cognitive deficits and impaired olfactory function are observed in early stages of Huntington's disease (HD). The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is strongly associated with plastic events in the brain. During adulthood, it is most abundantly expressed in the hippocampus and the piriform cortex, which are involved in cognition and olfaction, respectively. We show that the numbers of PSA-NCAM-positive cells in the hippocampus and piriform cortex are dramatically reduced in the R6/1 and the R6/2 mouse models of HD. We hypothesize that the decrease in NCAM polysialylation reflects an impaired plasticity and might underlie some of the early symptoms in HD.
Experimental Neurology 2006 Dec 19; [Epub ahead of print]