Advanced Alzheimer disease is characterized by massive loss of neurons throughout the brain, but where does the process start? A new study of early AD brains indicates that the specialized Cajal-Retzius (CR) cells of cortical layer I may be especially hard hit in the initial stages of the disease. CR cells produce reelin, a protein important for cortical and hippocampal development and synaptogenesis, and their loss in AD might play a role in the synaptic and other pathologies associated with the disease, writes study author Stavros Baloyannis of the Aristotelian University, Thessaloniki, Greece.

In a paper appearing in the July International Journal of Neuroscience, Baloyannis describes a morphologic and morphometric analysis of CR cells in the temporal cortex of ten cases of AD, compared to ten brains from apparently healthy individuals. Light microscopy revealed many fewer CR cells and a dramatic reduction in their dendritic arbors. Using electron microscopy, Baloyannis could see that the remaining CR cells looked quite abnormal, with a decrease in mitochondrial number and disruption of their cristae structure. The cells made far fewer synaptic contacts with neurons in other cortical layers compared to CR cells in normal brains.

While many neurons are affected in AD, the observed alterations in CR cells exceed those seen in other cortical layers, such as in the Purkinje cells of the cerebellum, the author writes, arguing for a selective vulnerability of the CR cells. Loss of these cells could disrupt the established patterning of the cortex, or the balance of neurotransmitter activity in the region, he speculates. While most CR cells die off soon after birth in humans, there is some suggestion that the remaining cells, and the reelin they produce, could play a role later in life by contributing to synaptogenesis. Reelin deficiency leads to increased tau phosphorylation (see ARF related news story), a hallmark of AD brains, so these new results raise the intriguing possibility that some of the pathology of AD might be attributed to loss of reelin-producing cells. But other studies show little or no decrease in reelin immunoreactivity in the entorhinal cortex in people with AD, or in the brain of the APP/PS1 mouse (Riedel et al., 2003; Miettinen et al., 2004), keeping open the question of the role of CR cells and reelin in AD.—Pat McCaffrey

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References

News Citations

  1. Now Debuting on the Tau Stage . . . The <I>Dab1</I> Mutant Mouse

Paper Citations

  1. . Reelin-immunoreactive Cajal-Retzius cells: the entorhinal cortex in normal aging and Alzheimer's disease. Acta Neuropathol. 2003 Oct;106(4):291-302. PubMed.
  2. . Reelin-immunoreactivity in the hippocampal formation of 9-month-old wildtype mouse: effects of APP/PS1 genotype and ovariectomy. J Chem Neuroanat. 2005 Oct;30(2-3):105-18. PubMed.

Further Reading

Papers

  1. . Mitochondrial alterations in Alzheimer's disease. Am J Alzheimers Dis Other Demen. 2004 Mar-Apr;19(2):89-93. PubMed.
  2. . The cells of cajal-retzius: still a mystery one century after. Neuron. 2005 May 5;46(3):389-94. PubMed.

Primary Papers

  1. . Morphological and morphometric alterations of Cajal-Retzius cells in early cases of Alzheimer's disease: a Golgi and electron microscope study. Int J Neurosci. 2005 Jul;115(7):965-80. PubMed.