Lithium NP03 Treatment for Late-Stage Amyloidosis in Rat Model of Alzheimer’s Disease

by | Oct 13, 2020 | 2020, Alzheimer's Disease, Brain Health

Written by Angeline A. De Leon, Staff Writer. This study demonstrates how microdose NP03 lithium reduced markers of neuroinflammation and cellular oxidative stress during the post-plaque stage of amyloid pathology in a transgenic rat model of Alzheimer’s disease.

aging woman with nurseAlthough Alzheimer’s disease (AD) is one of the most well-studied neurodegenerative disorders, no formal curative treatment exists 1. AD involves the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles, which, over time, cause neuronal damage and atrophy of critical brain regions 2,3. Although lithium therapy has primarily been used for the treatment of mood disorders such as bipolar disorder 4, long-term treatment with lithium is also linked to reduced incident dementia 5. Clinical work has shown that microdose treatment with lithium can enhance attention and memory in patients with mild cognitive impairment 6, while observational research reports a lower rate of AD among individuals exposed to microdose lithium in drinking water for extended periods 7. NP03, a novel nano-dose formulation of lithium involving a water-in-oil microemulsion, offers higher bioavailability and enhanced absorption by the central nervous system, compared to standard lithium formulations 8. Experimental studies in rat models of AD show that NP03 has valuable neuroprotective properties which help attenuate neuroinflammation and disrupt early-stage cognitive impairment, even prior to the onset of Aβ accumulation 9,10. To determine whether NP03 treatment is associated with prophylactic effects during the post-plaque stage of AD as well, researchers at McGill University in Canada looked at the impact of NP03 treatment on cognition, amyloid plaque aggregation, and oxidative stress in transgenic rats transitioning to the plaque-bearing phase of AD pathology 11.

The experimental study was carried out with male and female McGill-R-Thy1-APP transgenic rats carrying a genetic mutation designed to display AD-like-amyloid pathology. Rats were administered NP03 (40 µg Li/kg; 1 mL/kg bodyweight) or a vehicle solution (1 mL/kg) once daily for 5 days a week for 3 months (spanning the pre-plaque to plaque formation stages of AD). Rats performed a novel object recognition test to assess remote working memory, and following anesthetization, plasma blood samples and brain tissue were collected. Electrochemiluminescent assays were used to measure levels of human Aβ38, Aβ40, Aβ42, and circulating pro-inflammatory cytokines. Mature Aβ plaques in the subiculum region of the hippocampus were visualized using a staining technique, and levels of interleukin-6 (IL-6) and chemokine ligand 1 (CXCL1) (markers of oxidative stress and neuroinflammation) were measured using immunohistochemistry methods.

Overall findings supported evidence of a prophylactic effect associated with NP03: rats receiving NP03 were seen to perform significantly better on the working memory test, compared to rats receiving the vehicle solution (p < 0.05). During the early Aβ post-plaque stage, NP03-treated rats also exhibited significantly lower Aβ aggregates in the hippocampal region, compared to vehicle-treated rats (t(13) = 3.001, p = 0.0051). Researchers also observed a significant relative decrease in soluble and insoluble cortical Aβ42 levels for NP03 rats (p = 0.0295, p = 0.0433, respectively). Finally, administration of NP03 vs. vehicle was associated with decreased levels of IL-6 and CXCL1 in the hippocampal regions of transgenic AD rats (p < 0.01 for both).

Present findings outline the general impact of lithium NP03 treatment on later stages of AD-like pathology in transgenic rats. Evidence suggests that NP03 microdoses can help attenuate memory deficits associated with AD pathology, reducing levels of mature Aβ plaques in key cortical regions like the hippocampus and reducing overall levels of Aβ42 (in plasma and in hippocampal formations). Moreover, treatment with NP03 was seen to effectively decrease markers of oxidative stress and neuroinflammation during the post-plaque stage of amyloid pathology. General findings suggest that microdose treatment with lithium NP03 is effective at reversing cognitive deficits and later stage amyloid pathology associated with AD. Replication of findings in human subjects is warranted, and additional pharmacological research is needed to identify the specific targeting sites of microdose lithium.

Wilson EN, Do Carmo S, Welikovitch LA, et al. NPO3, a microdose lithium formulation, blunts early amyloid post-plaque neuropathology in McGill-R-Th1-APP Alzheimer-like transgenic rats. Journal of Alzheimer’s Disease. 2020; 73: 723-739. DOI: 10.3233/JAD-190862.

© 2020 – IOS Press and the authors. All rights reserved

Posted October 13, 2020.

Angeline A. De Leon, MA, graduated from the University of Illinois at Urbana-Champaign in 2010, completing a bachelor’s degree in psychology, with a concentration in neuroscience. She received her master’s degree from The Ohio State University in 2013, where she studied clinical neuroscience within an integrative health program. Her specialized area of research involves the complementary use of neuroimaging and neuropsychology-based methodologies to examine how lifestyle factors, such as physical activity and meditation, can influence brain plasticity and enhance overall connectivity.

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