There is a common pattern to the pathological progression of Alzheimer disease (AD). Neurons in the top or superficial layers of the cerebral cortex succumb first—those in the deeper layers are affected later. For decades scientists have puzzled over this phenomenon. Is it something about the location or connectivity of the deeper neurons that protects them? Or, are they inherently more resistant to pathological insults? New findings suggest that inherent resistance could explain at least some of the pattern of AD progression. Writing in today’s Journal of Neuroscience, Karl Herrup and colleagues from Case School of Medicine and the University Memory and Aging Center, both in Cleveland, Ohio, report that deep layer cortical neurons isolated from embryonic brain tissue are more resistant to Aβ toxicity than cells from the superficial strata. Figuring out what makes the deeper cells more resistant could provide new clues to tackling this devastating disease.

Testing the susceptibility of different cortical layers to Aβ is no small feat. To address this, the researchers capitalized on an observation originally made 30 years ago. Researchers studying rat hippocampal neurons found that cells which best survive the trauma of being plucked from the brain and grown in dissociated cultures are those that have most recently completed their last cell division (see Banker and Cowan, 1977). Using BrdU to label and identify recently divided neurons, first author Rita Romito-DiGiacomo and colleagues show that this is also true for mouse cortical cultures. Thus, cultures begun at embryonic day 13.5 (E13.5) predominantly comprise cells destined for the deeper layer V and VI of the cortex, while those cultured at E16.5 contain layer IV neurons as well. The authors confirmed this by showing that E13.5 cultures were devoid of cells expressing the layer IV marker RORβ but robustly stained for the T box protein Tbr1, a layer V/VI marker. Cells cultured from E16.5 embryos, on the other hand, were a mixture of Tbr1- and RORβ-positive cells, indicating that these cultures had cells from layers IV, V and VI.

Armed with this knowledge, Romito-DiGiacomo and colleagues prepared various cortical cultures from mouse embryos between embryonic day 13 and 17, then exposed them to various concentrations of Aβ42 (0 to 30 μM). They found that neurons derived earlier, that is, those destined for the deeper layers, were more resistant to toxicity. For example, after 3 days in culture with 10 μM Aβ, E13 cells were still fully viable, whereas only about 50 percent of E16 cells survived. The results indicate that neurons destined for the upper cortical layers are intrinsically more susceptible to Aβ toxicity. In support of this, the authors found that Tbr1-positive cell loss in both E13- and E16-derived cells was minimal, despite the overall loss of cells in the latter population. This finding again speaks to the robustness of the Tbr1-positive or layer V/VI cells.

Finding out why layer V/VI cells are more resistant to Aβ might prove invaluable in the fight against AD. Tbr1 itself might confer some resistance, note the authors, but there appear to be thousands of proteins that may play a potential role. Herrup and colleagues probed Aβ-treated E13.5 cultures with a gene chip array that detects 34,000+ genes. They found that expression of over 1,000 genes changed by a factor of two or more. Most were downregulated, but 45 were upregulated. They also found that in untreated cells, expression of 132 transcripts differs between E13.5- and E16.5-derived cells. Some of these proteins may hold the key to understanding the resilience of deep layer neurons to AD pathology.

One other explanation for the differential susceptibility of cortical layers to AD pathology is that neural connections may somehow influence progression. This work does not discount that incoming and outgoing connections may have some influence, but “the in vitro model suggests that there are at least some neuron-intrinsic factors that are likely to be at play in determining the pattern of neurodegeneration seen in the human AD brain,” write the authors.—Tom Fagan


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Paper Citations

  1. . Rat hippocampal neurons in dispersed cell culture. Brain Res. 1977 May 13;126(3):397-42. PubMed.

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Primary Papers

  1. . Effects of Alzheimer's disease on different cortical layers: the role of intrinsic differences in Abeta susceptibility. J Neurosci. 2007 Aug 8;27(32):8496-504. PubMed.