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Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. 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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University of Zurich
Sant Pau Biomedical Research Institute, Memory Unit
McGill University
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.
References:
Ferretti MT, Bruno MA, Ducatenzeiler A, Klein WL, Cuello AC. Intracellular Aβ-oligomers and early inflammation in a model of Alzheimer's disease. Neurobiol Aging. 2011 Mar 15; PubMed.
Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. J Neuroinflammation. 2012;9:62. PubMed.
Hanzel CE, Pichet-Binette A, Pimentel LS, Iulita MF, Allard S, Ducatenzeiler A, Do Carmo S, Cuello AC. Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2249-62. Epub 2014 Mar 28 PubMed.
Ferretti MT, Cuello AC. Does a pro-inflammatory process precede Alzheimer's disease and mild cognitive impairment?. Curr Alzheimer Res. 2011 Mar;8(2):164-74. PubMed.
Breitner JC, Baker LD, Montine TJ, Meinert CL, Lyketsos CG, Ashe KH, Brandt J, Craft S, Evans DE, Green RC, Ismail MS, Martin BK, Mullan MJ, Sabbagh M, Tariot PN, . Extended results of the Alzheimer's disease anti-inflammatory prevention trial. Alzheimers Dement. 2011 Jul;7(4):402-11. PubMed.
Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL, Araoz C. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7611-5. PubMed.
Wilcock DM, Hurban J, Helman AM, Sudduth TL, McCarty KL, Beckett TL, Ferrell JC, Murphy MP, Abner EL, Schmitt FA, Head E. Down syndrome individuals with Alzheimer's disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer's disease. Neurobiol Aging. 2015 Sep;36(9):2468-74. Epub 2015 May 30 PubMed.
Iulita MF, Caraci F, Cuello AC. A Link Between Nerve Growth Factor Metabolic Deregulation and Amyloid-β-Driven Inflammation in Down Syndrome. CNS Neurol Disord Drug Targets. 2016;15(4):434-47. PubMed.
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