. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 6;352(6286):712-6. Epub 2016 Mar 31 PubMed.


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  1. This is another thought-provoking study led by Stevens, Selkoe, and Lemere showing an oligomeric Aβ-induced, complement-dependent loss of synapses in early (i.e., pre-plaque) stages of amyloid pathology in transgenic APP models of cerebral amyloidosis. The results nicely fit with our original observations of subtle, pre-plaque CNS inflammation in Alzheimer’s disease-like pathology (Ferretti et al., 2011). In particular, they provide a mechanistic explanation for our finding of intermediate microglia activation associated with incipient cognitive deficits and intraneuronal Aβ-oligomeric material at the pre-plaque stage in APP mouse (Ferretti et al., 2011 and 2012) and rat models (Hanzel et al., 2014).

    Evidence for early, disease-aggravating, pre-plaque pro-inflammatory process is emerging (Ferretti and Cuello, 2011). As a case in point, in the Alzheimer’s Disease Anti-inflammatory Prevention Trial, NSAIDs (naproxen or celecoxib) were effective in improving cognition only at the asymptomatic phase, and not in individuals with overt Alzheimer’s symptoms (Breitner et al., 2011). In addition, earlier studies in Down’s syndrome revealed increased astrogliosis and IL-1 levels at the neonatal stage, decades before the development of advanced Alzheimer’s pathology (Griffin et al., 1989). In a recent investigation, Wilcock and colleagues further demonstrated that the Alzheimer-asymptomatic stage in Down’s syndrome is characterized by exacerbated neuroinflammation (Wilcock et al., 2015). In line with this observation, our work in collaboration with Dr. Caraci (University of Catania, Italy) and Dr. Cuello (McGill University, Canada) indicates elevation of inflammatory markers at the pre-dementia stage in individuals with trisomy 21, correlating with prospective cognitive decline over a two-year period (Iulita et al., 2016, and under revision). 

    The role of inflammation during the progression of the amyloid pathology remains to be elucidated. As the authors point out, complement activation might play completely opposite roles at different stages of the pathology; it is very likely that, while early complement activation leads to detrimental synaptic loss, late plaque-associated activation supports beneficial amyloid phagocytosis. Experiments in older APP-PS1 mice, as well as other transgenic models, would help address this point. Indeed, the characterization of microglial activation in early and late stages of amyloid pathology is crucial to identify suitable therapeutic targets.


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