BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology

E. N. Wilson; S. Do Carmo; M. F. Iulita; H. Hall; A. Ducatenzeiler; A. R. Marks; S. Allard; D. T. Jia; J. Windheim; A. C. Cuello

doi:10.1038/tp.2017.169

BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology

E. N. Wilson, S. Do Carmo, M. F. Iulita, H. Hall, A. Ducatenzeiler, A. R. Marks, S. Allard, D. T. Jia, J. Windheim, A. C. Cuello^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

Lithium is first-line therapy for bipolar affective disorder and has recently been shown to have protective effects in populations at risk for Alzheimer's disease (AD). However, the mechanism underlying this protection is poorly understood and consequently limits its possible therapeutic application in AD. Moreover, conventional lithium formulations have a narrow therapeutic window and are associated with a severe side effect profile. Here we evaluated a novel microdose formulation of lithium, coded NP03, in a well-characterized rat model of progressive AD-like amyloid pathology. This formulation allows microdose lithium delivery to the brain in the absence of negative side effects. We found that NP03 rescued key initiating components of AD pathology, including inactivating GSK-3β, reducing BACE1 expression and activity, and reducing amyloid levels. Notably, NP03 rescued memory loss, impaired CRTC1 promoter binding of synaptic plasticity genes and hippocampal neurogenesis. These results raise the possibility that NP03 be of therapeutic value in the early or preclinical stages of AD.

Original language	English (US)
Article number	e1190
Journal	Translational psychiatry
Volume	7
Issue number	8
DOIs	https://doi.org/10.1038/tp.2017.169
State	Published - Aug 1 2017

Funding

This work was supported by grants from the Canadian Institutes of Health Research grant number: 102752 and Centres of Excellence in Neurodegeneration grant number: 01074. We thank Dr A Frosst, the Frosst family and Merck Canada for their continuing support. We thank Dr. Jean-Benoit Charron for his help with chromatin immunoprecipitation experiments. SDC is the holder of the Charles E Frosst/Merck Research Associate position. MFI was the recipient of a Biomedical Doctoral Award from the Alzheimer Society of Canada (2011-2014). HH is the holder of a Fonds de Recherche Sante Quebec Postdoctoral Fellowship. ACC is the holder of the Charles E Frosst/Merck-endowed Chair in Pharmacology and is a Team Leader for the Canadian Consortium on Neurodegeneration in Aging.

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Biological Psychiatry

Access to Document

10.1038/tp.2017.169

Cite this

@article{97be6adb994946159e6a0041b25e034f,

title = "BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology",

abstract = "Lithium is first-line therapy for bipolar affective disorder and has recently been shown to have protective effects in populations at risk for Alzheimer's disease (AD). However, the mechanism underlying this protection is poorly understood and consequently limits its possible therapeutic application in AD. Moreover, conventional lithium formulations have a narrow therapeutic window and are associated with a severe side effect profile. Here we evaluated a novel microdose formulation of lithium, coded NP03, in a well-characterized rat model of progressive AD-like amyloid pathology. This formulation allows microdose lithium delivery to the brain in the absence of negative side effects. We found that NP03 rescued key initiating components of AD pathology, including inactivating GSK-3β, reducing BACE1 expression and activity, and reducing amyloid levels. Notably, NP03 rescued memory loss, impaired CRTC1 promoter binding of synaptic plasticity genes and hippocampal neurogenesis. These results raise the possibility that NP03 be of therapeutic value in the early or preclinical stages of AD.",

author = "Wilson, {E. N.} and {Do Carmo}, S. and Iulita, {M. F.} and H. Hall and A. Ducatenzeiler and Marks, {A. R.} and S. Allard and Jia, {D. T.} and J. Windheim and Cuello, {A. C.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

month = aug,

day = "1",

doi = "10.1038/tp.2017.169",

language = "English (US)",

volume = "7",

journal = "Translational psychiatry",

issn = "2158-3188",

publisher = "Springer Nature",

number = "8",

}

TY - JOUR

T1 - BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology

AU - Wilson, E. N.

AU - Do Carmo, S.

AU - Iulita, M. F.

AU - Hall, H.

AU - Ducatenzeiler, A.

AU - Marks, A. R.

AU - Allard, S.

AU - Jia, D. T.

AU - Windheim, J.

AU - Cuello, A. C.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Lithium is first-line therapy for bipolar affective disorder and has recently been shown to have protective effects in populations at risk for Alzheimer's disease (AD). However, the mechanism underlying this protection is poorly understood and consequently limits its possible therapeutic application in AD. Moreover, conventional lithium formulations have a narrow therapeutic window and are associated with a severe side effect profile. Here we evaluated a novel microdose formulation of lithium, coded NP03, in a well-characterized rat model of progressive AD-like amyloid pathology. This formulation allows microdose lithium delivery to the brain in the absence of negative side effects. We found that NP03 rescued key initiating components of AD pathology, including inactivating GSK-3β, reducing BACE1 expression and activity, and reducing amyloid levels. Notably, NP03 rescued memory loss, impaired CRTC1 promoter binding of synaptic plasticity genes and hippocampal neurogenesis. These results raise the possibility that NP03 be of therapeutic value in the early or preclinical stages of AD.

AB - Lithium is first-line therapy for bipolar affective disorder and has recently been shown to have protective effects in populations at risk for Alzheimer's disease (AD). However, the mechanism underlying this protection is poorly understood and consequently limits its possible therapeutic application in AD. Moreover, conventional lithium formulations have a narrow therapeutic window and are associated with a severe side effect profile. Here we evaluated a novel microdose formulation of lithium, coded NP03, in a well-characterized rat model of progressive AD-like amyloid pathology. This formulation allows microdose lithium delivery to the brain in the absence of negative side effects. We found that NP03 rescued key initiating components of AD pathology, including inactivating GSK-3β, reducing BACE1 expression and activity, and reducing amyloid levels. Notably, NP03 rescued memory loss, impaired CRTC1 promoter binding of synaptic plasticity genes and hippocampal neurogenesis. These results raise the possibility that NP03 be of therapeutic value in the early or preclinical stages of AD.

UR - http://www.scopus.com/inward/record.url?scp=85026783851&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026783851&partnerID=8YFLogxK

U2 - 10.1038/tp.2017.169

DO - 10.1038/tp.2017.169

M3 - Article

C2 - 28763060

AN - SCOPUS:85026783851

SN - 2158-3188

VL - 7

JO - Translational psychiatry

JF - Translational psychiatry

IS - 8

M1 - e1190

ER -

BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this