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conferenceseries.com
Volume 8 Journal of Alzheimers Disease & Parkinsonism
ISSN: 2161-0460 Euro Dementia 2018
May 24-25, 2018
May 24-25, 2018 | Vienna, Austria
11th International Conference on
Alzheimers Disease & Dementia
Neuropathophysiology cross-talk between Alzheimer’s and Parkinson’s disease
Li Zeng1, 5, Zhongcan Chen1, Wei Zhang1, Ling Ling Chua 1, Chou Chai1, Rong Li2, Lin Lin3, 4, Zhen Cao1, Dario C Angeles1, Lawrence W Stanton 3, Jianhe
Peng2, Zhi Dong Zhou1, 5, Kah Leong Lim1, 4, 5 and Eng King Tan1, 5
1National Neuroscience Institute, Singapore
2The Experimental Therapeutics Centre (ETC)—A*STAR, Singapore
3Genome Institute of Singapore (GIS)—A*STAR, Singapore
4National University of Singapore, Singapore
5DUKE-NUS Medical School, Singapore
Background: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of familial and sporadic
Parkinson’s disease (PD). Amyloid precursor protein (APP) is an important molecule in Alzheimer’s disease (AD). Although
recent research revealed that there might be common pathophysiological and genetic links between these two diseases, little is
known about the potential biological interplay between LRRK2 and APP.
Materials &Methods: Here, we used LRRK2 G2019S mouse models and induced pluripotent stem cell (iPSC)–derived neurons
from PD patients to investigate the potential pathophysiological interplay between LRRK2 and APP in PD.
Results: We demonstrate here that LRRK2 interacts with APP and LC/MS/MS analysis revealed LRRK2 phosphorylates
APP at threonine-668 (T668). This in turn stimulates the production of the APP intracellular domain (AICD) and enhances
AICD nuclear translocation, which is associated with the dopaminergic neuron loss in aging LRRK2 G2019S mutant mice.
Importantly, we found that the expression of AICD exacerbates LRRK2 G2019S-induced neurotoxicity, whereas phospho-
mutant AICD (T668A) has no effect on LRRK2 G2019S-induced neuronal loss in vitro and in LRRK2 G2019S mutant mice.
Moreover, dopaminergic neurons generated from LRRK2 G2019S patient-derived induced pluripotent stem cells exhibit
significantly elevated phospho-APP T668 levels relative to their counterparts derived from healthy individuals. The level of
T668- phosphorylated APP is also significantly increased in LRRK2 G2019S post-mortem human brain tissues. Treatment
with LRRK2 inhibitors reduces phosphorylation at T668 in LRRK2 G2019S patient’s dopaminergic neurons and in LRRK2
G2019S mutant mice.
Discussion: APP and LRRK2 are physically and functionally linked, suggesting a shared pathway between the two most
common neurodegenerative diseases that may help explain their overlapping pathology, especially in advanced stages of the
respective disease.
Conclusions: APP is a substrate of LRRK2, and its phosphorylation promotes AICD function and neurotoxicity in PD.
Biograpy
Li Zeng is currently working as Senior Research Scientist and Principal Investigator at Neural Stem Cells Research Laboratory at National Neuroscience Institute,
Singapore. He has published more than 25 papers in reputed journals and has been serving as an Editorial Board Member of repute.
Li Zeng et al., J Alzheimers Dis Parkinsonism 2018, Volume 8
DOI:10.4172/2161-0460-C3-042