015 – Rescuing over-activated microglia by acetaminophen treatment restores cognitive performance in the Dp(16) mouse model of Down Syndrome
Bruno Pinto (1, 2) – Giovanni Morelli (2) – Andrea Petretto (3) – Martina Bartolucci (3) – Emilio Varea (4) – Tiziano Catelani (5) – Laura E Perlini (2*) – Laura Cancedda (2, 6*)
BIO@SNS, Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126. Pisa (1) – Local Micro-environment and Brain Development Laboratory, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova (2) – Core Facilities – Proteomics Laboratory, IRCCS Istituto Giannina Gaslini, Genova, Italy (3) – University of Valencia, Cellular Biology and Parasitology Department, Valencia, Spain (4) – Electron Microscopy Facility, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova (5) – Dulbecco Telethon Institute, Rome, Italy (6)
Microglia are the main immune cells of the brain and play important roles in mechanisms essential for cognitive functions. Down syndrome (DS) is caused by the presence of a supernumerary chromosome 21 (Chr21), and it represents the most frequent cause of genetic intellectual disability. Interestingly, some of the genes located on Chr21 are essential for the function of the immune system. However, it is not known whether microglial defects are involved in the cognitive deficits associated with DS. Here, we investigated the presence of microglial alterations and their implication in cognitive impairment in the DP16 mouse model of DS. At postnatal day 22, we found enlarged cell body and decreased ramifications in microglia of DP16 hippocampi, indicative of an activated state. Accordingly, we also found increased levels of pro-inflammatory cytokines in DP16 hippocampi. In addition, DP16 mice showed a reduced number of dendritic spines accompanied by a reduced frequency/amplitude of excitatory post-synaptic potentials and levels of drebrin- a protein important for dendritic spine morphology and function. Dp16 mice also showed cognitive deficits, as measured by the Novel Object Recognition (NOR) and Object Location (OLT) tests. Remarkably, depletion of defective microglia in DP16 mice by PLX3397 treatment was able to fully rescue cognitive defects in DP16 mice. Notably, treatment with the commonly used non-steroidal, anti-inflammatory drug acetaminophen (APAP) rescued microglia morphology and the cognitive performance of the DP mice. Interestingly, both PLX3397 and APAP treatments rescued the alteration in spine number and functions together with drebrin levels, suggesting that the dendritic spine alterations in DP16 animals may depend on the defective microglia. Altogether, our data suggest an involvement of microglia in the cognitive impairment observed in adult DS animals, possibly mediated by defective dendritic spines. Moreover, our study identifies microglia as a new target for safe therapeutic intervention by a common anti-inflammatory drug to rescue cognitive disabilities in individuals with DS.