Research Report CD40 ligation mediates plaque-associated tau phosphorylation in β-amyloid overproducing mice Vincent Laporte ⁎ , Ghania Ait-Ghezala, Claude-Henry Volmar, Christopher Ganey, Nowell Ganey, Marcie Wood, Michael Mullan The Roskamp Institute, 2040, Whitfield Avenue, Sarasota FL, 34243, USA ARTICLE INFO ABSTRACT Article history: Accepted 1 June 2008 Available online 19 June 2008 Neuritic dystrophy with amyloid burden and neurofibrillary tangles are pathological hallmarks of Alzheimer's disease. Genetic disruption of CD40 or CD40L alleviates amyloid burden, astrocytosis, and microgliosis in transgenic animal models of Alzheimer's disease. It has been reported that phosphorylated tau-positive dystrophic neurites are observed in transgenic mice over-expressing human mutant beta-amyloid precursor protein (Tg2576). Here, we studied the pattern of phosphorylated tau (labeled with AT8, CP13, PG5, and PHF1 antibodies) and plaques using immunohistochemical techniques. Phosphorylated tau- positive dystrophic neurites were exclusively associated with Congo red-positive plaques as previously reported. Further, we show that CD40L or CD40 deficiency reduces the mean ratio of dystrophic neurite area to congophilic plaque area and the level of expression of cdk5 and p35/p25 in mice. In addition, we show that in a human neuroblastoma cell line treated with CD40L, cdk5 and p35/p25 are increased. Together, our data suggest that CD40–CD40L interaction has an effect on tau phosphorylation independent of beta-amyloid pathology, and that this effect may occur through a decrease of cdk5 and p35/p25. © 2008 Elsevier B.V. All rights reserved. Keywords: Alzheimer's disease Amyloid CD40 CD40 ligand Mice Transgenic Tg2576 Microtubule-associated protein tau Hyperphosphorylated tau cdk5 Dystrophic neurite 1. Introduction Alzheimer's disease (AD) is characterized by the extracellular deposition of amyloid β-peptide (Aβ) (which is derived from the processing of the β-amyloid precursor protein [APP]) in senile plaques and intracellular accumulation of neurofibril- lary tangles composed principally of phosphorylated tau protein (Selkoe, 2001). Abnormal phosphorylation of tau proteins is the most established cause of dysfunctional tau in AD and occurs at 19 specific amino acids throughout tau sequence (Quadros et al., 2007). Abnormal neuronal processes known as dystrophic neurites (DN) are found closely associated with the amyloid deposits. Once DN are embedded in the edge of amyloid plaques, the latter are referred to as neuritic plaques. In severe AD cases, DN are immunolabeled for phosphorylated tau (Dickson et al., 2005; Su et al., 1998). Transgenic mice Tg2576 expressing human APP with the Swedish mutation (APP sw , K670N/M671L) have been a useful tool for studying AD-like brain amyloidosis in the past (Hsiao, 1998; Mullan et al., 1992). Unfortunately, Tg2576 mice do not develop neurofibrillary tangles or neuronal loss like human AD patients. However, DN have been located in the vicinity of amyloid deposits in the Tg2576, suggesting that these mice are a good model of neuritic dystrophy caused by amyloid deposition (Noda-Saita et al., 2004; Otth et al., 2002; Tomido- koro et al., 2001). Phosphorylated tau-positive DN were BRAIN RESEARCH 1231 (2008) 132 – 142 ⁎ Corresponding author. Fax: +1 941 752 2948. E-mail address: vlaporte@rfdn.org (V. Laporte). 0006-8993/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2008.06.032 available at www.sciencedirect.com www.elsevier.com/locate/brainres