The long-term goal of this project is to further our understanding of the underlying mechanisms leading to memory loss in Alzheimer's disease (AD). In this study, we propose to investigate the composition and mechanisms of action of beta-amyloid (A?) assemblies disrupting learning and memory in mice and humans. We have previously demonstrated strong associations between A?*56, an endogenously formed 56-kDa A? assembly, and memory dysfunction in the Tg2576 APP transgenic mouse line and shown that purified A?*56 disrupts cognitive function when injected into the lateral ventricles of young, healthy rats. Unpublished data revealed that A?*56 physically interacts with NMDA receptor (NMDAR) complexes and evokes Ca2+ transients in primary neuronal cultures. In addition, we have detected multiple A? oligomers including A?*56 in humans at stages preceding clinical AD (i.e. pathological aging and mild cognitive impairment, MCI). Together, these observations have led us to propose that Alzheimer's disease begins as a disorder of synaptic function, triggered when A?*56 disrupts NMDAR-mediated synaptic physiology. In parallel other A? oligomers (dimers, trimers and A?-derived diffusible ligands, ADDLs) have displayed specific synaptotoxic and/or cytotoxic effects. Of recent focus, A? dimers were found in close association with amyloid plaques and are among the leading culprits mediating the neurotoxicity observed within the microenvironment of deposited amyloid, which has been proposed to underlie some aspects of dementia in AD. The diversity of these A?-induced effects suggests that multiple oligomeric A? species trigger specific mechanisms at different stages of the disease. Efforts to clarify this complex situation may reconcile disputes and resolve confusion concerning the relevance and significance of low-n versus high-n oligomers. The goal of the proposed study is to better understand the roles of distinct A? oligomers in the pathogenesis and progression of AD. To test this hypothesis, four aims are proposed: 1) determine whether specific A? oligomers are correlated with clinical status or cognitive decline in humans;2) identify molecular targets of specific A? oligomers;3) determine whether and how A? oligomers modulate NMDARs function in vitro;4) examine how A? oligomers affect NMDAR-dependent LTP in vivo.
Understanding the mechanisms by which A? oligomers impair memory function is important for preventing AD, an ominous public health menace. Isolating and characterizing A? oligomers in humans may facilitate early diagnosis and prevention of AD. Determining how multiple A? oligomers trigger mechanisms at different stages of the disease may not only provide therapeutic targets for AD but also address why AD affects specific neural circuits in the brain.
|Liu, Peng; Reichl, John H; Rao, Eshaan R et al. (2017) Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-? Protein Precursor Transgenic Mice. J Alzheimers Dis 56:743-761|
|Sherman, Mathew A; LaCroix, Michael; Amar, Fatou et al. (2016) Soluble Conformers of A? and Tau Alter Selective Proteins Governing Axonal Transport. J Neurosci 36:9647-58|
|Liu, Peng; Reed, Miranda N; Kotilinek, Linda A et al. (2015) Quaternary Structure Defines a Large Class of Amyloid-? Oligomers Neutralized by Sequestration. Cell Rep 11:1760-71|
|Weitzner, Daniel S; Engler-Chiurazzi, Elizabeth B; Kotilinek, Linda A et al. (2015) Morris Water Maze Test: Optimization for Mouse Strain and Testing Environment. J Vis Exp :e52706|
|Liu, Peng; Paulson, Jennifer B; Forster, Colleen L et al. (2015) Characterization of a Novel Mouse Model of Alzheimer's Disease--Amyloid Pathology and Unique ?-Amyloid Oligomer Profile. PLoS One 10:e0126317|
|Lesne, Sylvain E (2014) Toxic oligomer species of amyloid-? in Alzheimer's disease, a timing issue. Swiss Med Wkly 144:w14021|
|Qi, Yingjie; Klyubin, Igor; Harney, Sarah C et al. (2014) Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents. Acta Neuropathol Commun 2:175|
|Fowler, Stephanie W; Chiang, Angie C A; Savjani, Ricky R et al. (2014) Genetic modulation of soluble A? rescues cognitive and synaptic impairment in a mouse model of Alzheimer's disease. J Neurosci 34:7871-85|
|Ashe, Karen H; Aguzzi, Adriano (2013) Prions, prionoids and pathogenic proteins in Alzheimer disease. Prion 7:55-9|
|Handoko, Maureen; Grant, Marianne; Kuskowski, Michael et al. (2013) Correlation of specific amyloid-? oligomers with tau in cerebrospinal fluid from cognitively normal older adults. JAMA Neurol 70:594-9|
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