P1‐345: The shortening of somatostatin receptor‐3‐bearing primary cilia of neurons in the dentate gyri of Aβ_1‐42 and P301L‐tau accumulating transgenic Alzheimer‐mice but not in mice accumulating only Aβ_1‐42

One of the most consistent features of human AD brains and the brains of AD-transgenic mice along with Aβ1-42 plaques and tau tangles is a reduced somatostatin (SST) content. While most of the 5 SST receptors are conventionally located in cell membranes of a variety of cells including neurons, one of them, SSTR3, is localized to each mature dentate gyrus (DG) granule cell's primary cilium by its unique ciliary-localization amino acid sequence. The SSTR3-bearing mature neurons in the DG's granular layer are the first recipients and initial processors of polymodal information flowing into the hippocampus along the perforant pathway from the entorhinal cortex. Thus, any changes of the DG granular cells' SSTR3s and/or SSTR3 signaling via the cilium might affect memory formation. In the present study we sought determine if Aß and or tau would affect primary cilia. For this, brains from wild-type, triple-transgenic (3xTg) and double transgenic mice (6-8, 14-18, and 20-24 months old) were removed and one half of the brain was cryo-sectioned and subjected to immunohistochemical analyses using SSTR3-selective antibody. There was a replicable, highly significant shortening of the SSTR3-bearing primary cilia of DG cells in the brains of AD-triple transgenic mice (3xTg-AD) harbouring human PS1M146V, APPSwe and tau P301L transgenes. There were no changes in the cilial length in age-matched wild-type mice at any of the ages tested. On the other hand there was no loss of cilia as reflected in a constant cilium to cell ratio of 0.9 in both wild-type and the 3xTg-AD mice. Interestingly, no significant changes in cilial length were seen in double transgenic mice harbouring mutant human PSEN1deE9 and human AβPPSwe compared to corresponding wild type mice. There was age-dependent increase in Aß1-42 levels in both the transgenic mice suggesting that Aß load itself did not affect cilial growth. Since the difference between triple and double transgenic animals is accumulating mutant tau, it is likely that overexpressed tau is influencing SSTR-3 cilial growth in the dentate gyral granule cells of 3xTg mice by affecting cytoskeletal structure and delivery of SSTR3 proteins to the primary cilia.

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