Reduction of the immunostainable length of the hippocampal dentate granule cells’ primary cilia in 3xAD-transgenic mice producing human Ab 1-42 and tau Balu Chakravarthy a,⇑ , Chantal Gaudet a , Michel Ménard a , Leslie Brown a , Trevor Atkinson a , Frank M. LaFerla b , Shingo Ito a , Ubaldo Armato c , Ilaria Dal Prà c , James Whitfield a a Human Health Therapeutics, National Research Council of Canada, Ottawa, ON, Canada b Department of Neurobiology and Behavior, University of California, Irvine, CA, United States c Department of Life and Reproduction Sciences, University of Verona Medical School, Verona, Italy article info Article history: Received 31 August 2012 Available online 17 September 2012 Keywords: Alzheimer’s disease Dentate granule cells Primary cilium p75 NTR Somatostatin receptor 3 (SSTR3) 3xTg-AD mice abstract The hippocampal dentate gyrus is one of the two sites of continuous neurogenesis in adult rodents and humans. Virtually all dentate granule cells have a single immobile cilium with a microtubule spine or axoneme covered with a specialized cell membrane loaded with receptors such as the somatostatin receptor 3 (SSTR3), and the p75 neurotrophin receptor (p75 NTR ). The signals from these receptors have been reported to stimulate neuroprogenitor proliferation and the post-mitotic maturation of newborn granule cells into functioning granule cells. We have found that in 6–24-months-old triple transgenic Alzheimer’s disease model mice (3xTg-AD) producing both Ab 1-42 and the mutant human tau protein tau P301L, the dentate granule cells still had immunostainable SSTR3- and p75 NTR -bearing cilia but they were only half the length of the immunostained cilia in the corresponding wild-type mice. However, the immunostainable length of the granule cell cilia was not reduced either in 2xTg-AD mice accumulat- ing large amounts of Ab 1-42 or in mice accumulating only a mutant human tau protein. Thus it appears that a combination of Ab 1-42 and tau protein accumulation affects the levels of functionally important receptors in 3xTg-AD mice. These observations raise the important possibility that structural and func- tional changes in granule cell cilia might have a role in AD. Crown Copyright Ó 2012 Published by Elsevier Inc. All rights reserved. 1. Introduction Each hippocampal granule cell in the mature rodent has a single signaling antenna—a ‘primary’ cilium [1]. This organelle consists of a spine (axoneme) of 9 microtubule doublets that serve as track- ways for the traffic of components to and from the basal body by the intraflagellar transport (IFT) machinery. Primary cilia are wrapped in a specialized plasma membrane bearing various recep- tors and their signaling machinery, the signals from which are be- lieved to drive diverse functions ranging from neurogenesis, maturation to memory encoding [2–8]. One of these receptors is the SSTR3 (somatostatin type 3 receptor) which is specifically localized to primary cilia in various types of cell including the den- tate granule cells [4,9–14]. SSTR3 receptors are loaded by maturing granule cells into their primary cilia to send signals to drive func- tions such as memory formation as measured by the ability to recognize novelty [4]. Another receptor is p75 NTR which we have recently shown to also be localized to the granule cell cilia along with SSTR3 [15] where it likely provides signals to drive granule cell progenitor proliferation in the dentate sub-granular zone (SGZ), but it may also have other roles because virtually all postmi- totic, mature granule cells have p75 NTR -loaded cilia [8]. In the present study we show that the accumulation of human amyloid ß (Ab 1-42 ) and mutant tau protein, the dual initiators and drivers of the events leading to AD, together reduce the immu- nostainable length of the SSTR3/p75 NTR -bearing primary cilia in the mouse dentate gyri of AD-model mice. In 2xTg-AD mice accu- mulating only Ab cleaved from a mutant human APP, and in tau- Tg mice producing only a mutant human tau P301S protein [16,17], the cilial length was the same (i.e., 4–5-lm average) as in the cor- responding wild type mice. However, the p75 NTR -SSTR3-bearing cilia are much shorter in 3xTg-AD mice accumulating human Ab 1-42 and mutant human tau protein. Thus, this is hopefully a heuristic example of Ab 1-42 and mutant tau collaborating to cause the severely reduced the cilium-based signaling for neurogenesis, memory and other mature functions in these AD-model mice [18]. 0006-291X/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bbrc.2012.09.056 ⇑ Corresponding author. Address: National Research Council, 1200 Montreal Road, Building M-54, Institute for Biological Sciences, Ottawa, ON, Canada K1A 0R6. Fax: +1 613 941 4475. E-mail address: Balu.Chakravarthy@nrc-cnrc.gc.ca (B. Chakravarthy). Biochemical and Biophysical Research Communications 427 (2012) 218–222 Contents lists available at SciVerse ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc