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.

Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain

“…Interestingly, elevated levels of CCL3, which were also observed in Aβ-burdened neurons, produce aberrant neural firing patterns in vitro (78) and suppress synaptic transmission and behavioral performance in vivo (79). The consequences of sustained neuronal inflammation and excessive neuroglial interactions may explain many of the functional deficits observed in preplaque Tg animal models, including our own: Even in the absence of extracellular plaques, the McGill-R-Thy1-APP rat displays substantial LTP impairment and cognitive dysfunction (24,29,30,80,81).…”

Lithium to Treat – Or Prevent – Dementia: A Short Discussion

“…There are even potential options for reconsidering the formulation of lithium itself [20]. A novel micro dose formulation of lithium, coded NP03, was assessed in a rat study and found to address key components of Alzheimer's disease pathology (including GSK-3 inhibition and reducing amyloid levels, without significant renal impairment.…”

Lithium as a disease-modifying agent for prion diseases

“…In the rat model of AD, NP03 reversed the deficits in novel object recognition, inactivated GSK-3β through phosphorylation at Ser9, rescued the native β-catenin protein levels, and decreased BACE1 gene expression. NP03 also reduced the levels of toxic Aβ42 peptides and induced neurogenesis, as indicated by the increase in doublecortin expression in hippocampus tissue sections 24 . Based on these encouraging results, we wanted to determine whether treatment with low doses of lithium (using NP03) could improve prion-related pathology in a commonly used model of prion disease obtained by inoculating ME7 prion-infected brain homogenates in the brain of C57BL/6J mice.…”

“…This formulation offers the possibility to lower by several hundred times the quantity of lithium to be used compared with conventional formulations. NP03 has already been tested in the YAC128 mouse model of HD 11 and in a well-characterized rat model of AD 24 . In the YAC128 mouse model, NP03 ameliorated the motor and neuropathological phenotypes and improved various biochemical features 11 .…”