P2‐222: Changes in the expression of somatostatin 3 receptor (SSTR3) and p75NTR in the hippocampal primary cilia of Alzheimer's disease transgenic mice

The dentate gyrus's subgranular zone is one of two neurogenic regions in adult rodent and human brains. The hyperexcitable young granule cells are able to start the hippocampal encoding of novel polymodal inputs from the entorhinal cortex into new memories. Each of these cells extends a single cilium into its extracellular environment. These granule cells are known to localize somatostatin receptor 3 (SSTR3) to their cilia which play a role in postmitotic development and memory recoding. Using SSTR3- and p75- selective antibodies we have carried out immunohistochemical staining of hippocampi from wild type and Alzheimer disease (AD) transgenic mice. We have seen that granule cell cilia in mice also bear p75 receptors, signals from which may play a role in progenitor cell proliferation and neurogenesis. We have found cilial changes in AD mice that may be relevant to human AD. In the 2xTg-AD mice, that only produce human Aß1-42, the granule cell cilia bearing SSTR3 and p75 appear to be the same as in wild-type mice. Similarly, in tau transgenic mice expressing only mutant human tau (P301S) the cilia appear to be the same as in wild type mice. However, in 3xTg-AD mice producing both human Aß1-42 and mutant tau (P301L) the cilia with the two receptors are severely truncated, suggesting that both Aß1-42 and tau protein are required for cilial “shortening”. A possible role for the involvement of cilia in AD is suggested by the recently reported hippocampal dysgenesis in persons with Bardet-Biedl syndrome, a proven “ciliopathy”, and the commonly reduced SST level in AD brains with a consequently reduced signaling from cilial SSTR3. Reduced levels of proliferogenic p75 and the maturation-driving SSTR3 in the truncated primary cilia of an Aß1-42 and tau-accumulating AD hippocampus would severely impair both neurogenesis and memory formation as reported in 3xTg mice. It is important now to find out whether human dentate granule cells also have primary cilia expressing SSTR3 and p75 receptors, and whether the same cilial changes happen in human AD brains as in 3xTg-AD mice.

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