The long-term goal of this project is to better understand the contribution of soluble form(s) of alpha-synuclein (?Syn) in Alzheimer's disease (AD). Our recently published findings suggest that (i) intraneuronal soluble ?Syn is abnormally elevated in AD brains in absence of deposited ?Syn, (ii) soluble ?Syn is a quantitatively better correlate of cognitive function than soluble amyloid-beta (A?) and tau in humans, (iii) overexpression of ?Syn leads to cognitive impairment in mice, (iv) elevation of ?Syn leads to decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles and (v) a synergism between A?/APP and human tau appears to be responsible for the abnormal elevation of soluble ?Syn in transgenic mice. In this study, we propose to determine whether soluble non-fibrillar forms of ?Syn are modulating cognitive decline in mice and to unravel the synaptic mechanism by which ?Syn might be impairing memory. The overall objective of this application is to identify the role of soluble ?Syn molecule(s) and its(their) relative contribution(s) to AD. Altogether, our observations suggest that AD might not be a two-protein disorder (i.e. A? and tau) but instead a three-pronged attack of neuronal synapses by A?, tau and soluble ?Syn. To test this provocative hypothesis, three questions regrouped under three aims are proposed: 1) Does deleting the ?Syn gene SNCA from APP mice improve behavior, pathology and synaptic vesicle composition? 2) What form(s) of soluble ?Syn is/are associated with cognitive impairment in brains of ?Syn transgenic animals and in subjects with AD? 3) What is the mechanism(s) by which soluble ?Syn species alter presynaptic vesicle composition?
Soluble a-synuclein is a modulator of Alzheimer's disease pathophysiology Project Narrative If our hypothesis is correct, Alzheimer's disease (AD) would not be considered a neurological disorder involving two key proteins, i.e. amyloid- (A) and tau, but instead a disease triggered by abnormal changes in three key proteins: A, tau and a-synuclein (aSyn). In addition, our findings could explain why drugs effective in current AD mouse models, which harbor amyloid plaques without human wild-type tau or wild-type aSyn, do not work in humans.
|Khan, Shahzad S; LaCroix, Michael; Boyle, Gabriel et al. (2018) Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons. Acta Neuropathol :|
|Chiang, Angie C A; Fowler, Stephanie W; Reddy, Rohit et al. (2018) Discrete Pools of Oligomeric Amyloid-? Track with Spatial Learning Deficits in a Mouse Model of Alzheimer Amyloidosis. Am J Pathol 188:739-756|
|Larson, Megan E; Greimel, Susan J; Amar, Fatou et al. (2017) Selective lowering of synapsins induced by oligomeric ?-synuclein exacerbates memory deficits. Proc Natl Acad Sci U S A 114:E4648-E4657|
|Amar, Fatou; Sherman, Mathew A; Rush, Travis et al. (2017) The amyloid-? oligomer A?*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. Sci Signal 10:|
|Alfonso, Stephanie I; Callender, Julia A; Hooli, Basavaraj et al. (2016) Gain-of-function mutations in protein kinase C? (PKC?) may promote synaptic defects in Alzheimer's disease. Sci Signal 9:ra47|
|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|
|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|
|Lesne, Sylvain E (2014) Toxic oligomer species of amyloid-? in Alzheimer's disease, a timing issue. Swiss Med Wkly 144:w14021|
|Larson, Megan E; Lesné, Sylvain E (2012) Soluble A? oligomer production and toxicity. J Neurochem 120 Suppl 1:125-39|