TY - JOUR
T1 - Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons
AU - Khan, Shahzad S.
AU - LaCroix, Michael
AU - Boyle, Gabriel
AU - Sherman, Mathew A.
AU - Brown, Jennifer L.
AU - Amar, Fatou
AU - Aldaco, Jacqeline
AU - Lee, Michael K.
AU - Bloom, George S.
AU - Lesné, Sylvain E.
N1 - Publisher Copyright:
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - α-Synuclein (αSyn) histopathology defines several neurodegenerative disorders, including Parkinson’s disease, Lewy body dementia, and Alzheimer’s disease (AD). However, the functional link between soluble αSyn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted αSyn in APP transgenic mice modeling AD and mouse primary neurons. Our results demonstrate bidirectional modulation of behavioral deficits and pathophysiology by αSyn. Overexpression of human wild-type αSyn in APP animals markedly reduced amyloid deposition but, counter-intuitively, exacerbated deficits in spatial memory. It also increased extracellular amyloid-β oligomers (AβOs), αSyn oligomers, exacerbated tau conformational and phosphorylation variants associated with AD, and enhanced neuronal cell cycle re-entry (CCR), a frequent prelude to neuron death in AD. Conversely, ablation of the SNCA gene encoding for αSyn in APP mice improved memory retention in spite of increased plaque burden. Reminiscent of the effect of MAPT ablation in APP mice, SNCA deletion prevented premature mortality. Moreover, the absence of αSyn decreased extracellular AβOs, ameliorated CCR, and rescued postsynaptic marker deficits. In summary, this complementary, bidirectional genetic approach implicates αSyn as an essential mediator of key phenotypes in AD and offers new functional insight into αSyn pathophysiology.
AB - α-Synuclein (αSyn) histopathology defines several neurodegenerative disorders, including Parkinson’s disease, Lewy body dementia, and Alzheimer’s disease (AD). However, the functional link between soluble αSyn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted αSyn in APP transgenic mice modeling AD and mouse primary neurons. Our results demonstrate bidirectional modulation of behavioral deficits and pathophysiology by αSyn. Overexpression of human wild-type αSyn in APP animals markedly reduced amyloid deposition but, counter-intuitively, exacerbated deficits in spatial memory. It also increased extracellular amyloid-β oligomers (AβOs), αSyn oligomers, exacerbated tau conformational and phosphorylation variants associated with AD, and enhanced neuronal cell cycle re-entry (CCR), a frequent prelude to neuron death in AD. Conversely, ablation of the SNCA gene encoding for αSyn in APP mice improved memory retention in spite of increased plaque burden. Reminiscent of the effect of MAPT ablation in APP mice, SNCA deletion prevented premature mortality. Moreover, the absence of αSyn decreased extracellular AβOs, ameliorated CCR, and rescued postsynaptic marker deficits. In summary, this complementary, bidirectional genetic approach implicates αSyn as an essential mediator of key phenotypes in AD and offers new functional insight into αSyn pathophysiology.
KW - Alzheimer’s disease
KW - Amyloid-β
KW - Neuronal cell cycle re-entry
KW - Spatial memory
KW - Tau
KW - α-Synuclein
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UR - http://www.scopus.com/inward/citedby.url?scp=85049666433&partnerID=8YFLogxK
U2 - 10.1007/s00401-018-1886-z
DO - 10.1007/s00401-018-1886-z
M3 - Article
C2 - 29995210
AN - SCOPUS:85049666433
SN - 0001-6322
VL - 136
SP - 589
EP - 605
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 4
ER -