Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons

Shahzad S. Khan, Michael LaCroix, Gabriel Boyle, Mathew A Sherman, Jennifer L. Brown, Fatou Amar, Jacqeline Aldaco, Michael K Lee, George S. Bloom, Sylvain E Lesne

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)589-605
Number of pages17
JournalActa Neuropathologica
Volume136
Issue number4
DOIs
StatePublished - Oct 1 2018

Fingerprint

Synucleins
Phenotype
Neurons
Alzheimer Disease
Amyloid
Lewy Body Disease
Cell Cycle
Mouse Snca protein
Premature Mortality
Neurodegenerative Diseases
Transgenic Mice
Parkinson Disease

Keywords

  • Alzheimer’s disease
  • Amyloid-β
  • Neuronal cell cycle re-entry
  • Spatial memory
  • Tau
  • α-Synuclein

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons. / Khan, Shahzad S.; LaCroix, Michael; Boyle, Gabriel; Sherman, Mathew A; Brown, Jennifer L.; Amar, Fatou; Aldaco, Jacqeline; Lee, Michael K; Bloom, George S.; Lesne, Sylvain E.

In: Acta Neuropathologica, Vol. 136, No. 4, 01.10.2018, p. 589-605.

Research output: Contribution to journalArticle

Khan, Shahzad S. ; LaCroix, Michael ; Boyle, Gabriel ; Sherman, Mathew A ; Brown, Jennifer L. ; Amar, Fatou ; Aldaco, Jacqeline ; Lee, Michael K ; Bloom, George S. ; Lesne, Sylvain E. / Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons. In: Acta Neuropathologica. 2018 ; Vol. 136, No. 4. pp. 589-605.
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