TY - JOUR
T1 - Microdose lithium NP03 diminishes pre-plaque oxidative damage and neuroinflammation in a rat model of alzheimer’s-like amyloidosis
AU - Wilson, Edward N.
AU - Do Carmo, Sonia
AU - Iulita, M. Florencia
AU - Hall, Hélène
AU - Austin, Grant L.
AU - Jia, Dan T.
AU - Malcolm, Janice C.
AU - Foret, Morgan K.
AU - Marks, Adam R.
AU - Butterfield, D. Allan
AU - Cuello, A. Claudio
N1 - Publisher Copyright:
© 2018 Bentham Science Publishers.
PY - 2018
Y1 - 2018
N2 - Background: Microdose lithium is protective against Alzheimer’s disease (AD), although the precise mechanisms through which its protective effects are conferred remain unclear. Objective: To further examine the effects during the earliest stages of Aβ pathology, we evaluated whether NP03, a microdose lithium formulation, modulates Aβ-mediated oxidative damage and neuroinflammation when applied to a rat transgenic model of AD-like amyloidosis overexpressing amyloid precursor protein (APP). Method: McGill-R-Thy1-APP transgenic rats and wild-type littermates were treated with NP03 or vehicle formulation for 8 weeks beginning at 3 months of age-a phase preceding Aβ plaque deposition in the transgenic rats. Results: Oxidative and nitrosative stress markers, protein-bound 4-hydroxynonenal (HNE) and protein-resident 3-nitrotyrosine (3-NT), inflammatory cytokines production, as well as microglial recruitment towards Aβ-burdened neurons were assayed. NP03 significantly decreased cerebral HNE and 3-NT, and reduced production of pro-inflammatory cytokines in McGill-R-Thy1-APP transgenic rats. NP03 further reduced expression of microglia surface receptor Trem2 and led to a corresponding reduction in microglia recruitment towards Aβ-burdened neurons in the CA1 region of the hippocampus. Conclusion: These results suggest that NP03 may function to slow the AD-like pathology in part by modifying oxidative/nitrosative damage and neuroinflammation, raising the possibility that low doses of microencapsulated lithium might be of therapeutic-preventive value during very early or preclinical AD.
AB - Background: Microdose lithium is protective against Alzheimer’s disease (AD), although the precise mechanisms through which its protective effects are conferred remain unclear. Objective: To further examine the effects during the earliest stages of Aβ pathology, we evaluated whether NP03, a microdose lithium formulation, modulates Aβ-mediated oxidative damage and neuroinflammation when applied to a rat transgenic model of AD-like amyloidosis overexpressing amyloid precursor protein (APP). Method: McGill-R-Thy1-APP transgenic rats and wild-type littermates were treated with NP03 or vehicle formulation for 8 weeks beginning at 3 months of age-a phase preceding Aβ plaque deposition in the transgenic rats. Results: Oxidative and nitrosative stress markers, protein-bound 4-hydroxynonenal (HNE) and protein-resident 3-nitrotyrosine (3-NT), inflammatory cytokines production, as well as microglial recruitment towards Aβ-burdened neurons were assayed. NP03 significantly decreased cerebral HNE and 3-NT, and reduced production of pro-inflammatory cytokines in McGill-R-Thy1-APP transgenic rats. NP03 further reduced expression of microglia surface receptor Trem2 and led to a corresponding reduction in microglia recruitment towards Aβ-burdened neurons in the CA1 region of the hippocampus. Conclusion: These results suggest that NP03 may function to slow the AD-like pathology in part by modifying oxidative/nitrosative damage and neuroinflammation, raising the possibility that low doses of microencapsulated lithium might be of therapeutic-preventive value during very early or preclinical AD.
KW - Alzheimer’s disease
KW - Inflammation
KW - Microdose lithium
KW - Microglia
KW - Oxidative stress
KW - TREM2
UR - http://www.scopus.com/inward/record.url?scp=85055718120&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055718120&partnerID=8YFLogxK
U2 - 10.2174/1567205015666180904154446
DO - 10.2174/1567205015666180904154446
M3 - Article
C2 - 30182855
AN - SCOPUS:85055718120
SN - 1567-2050
VL - 15
SP - 1220
EP - 1230
JO - Current Alzheimer Research
JF - Current Alzheimer Research
IS - 13
ER -