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LISPRO mitigates β-amyloid and associated pathologies in Alzheimer's mice


Year of Publication:
Contact PI Name:
Jun Tan
Contact PI Affiliation:
Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
Ahsan Habib, Darrell Sawmiller, Song Li, Yang Xiang, David Rongo, Jun Tian, Huayan Hou, Jin Zeng, Adam Smith, Shengnuo Fan, Brian Giunta, Takashi Mori, Glenn Currier, Douglas R. Shytle
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Silver Endowment
Study Goal and Principal Findings:

Lithium has been marketed in the United States of America since the 1970s as a treatment for bipolar disorder. More recently, studies have shown that lithium can improve cognitive decline associated with Alzheimer's disease (AD). However, the current United States Food and Drug Administration-approved lithium pharmaceutics (carbonate and citrate chemical forms) have a narrow therapeutic window and unstable pharmacokinetics that, without careful monitoring, can cause serious adverse effects. Here, we investigated the safety profile, pharmacokinetics, and therapeutic efficacy of LISPRO (ionic co-crystal of lithium salicylate and l-proline), lithium salicylate, and lithium carbonate (Li2CO3). We found that LISPRO (8-week oral treatment) reduces β-amyloid plaques and phosphorylation of tau by reducing neuroinflammation and inactivating glycogen synthase kinase 3β in transgenic Tg2576 mice. Specifically, cytokine profiles from the brain, plasma, and splenocytes suggested that 8-week oral treatment with LISPRO downregulates pro-inflammatory cytokines, upregulates anti-inflammatory cytokines, and suppresses renal cyclooxygenase 2 expression in transgenic Tg2576 mice. Pharmacokinetic studies indicated that LISPRO provides significantly higher brain lithium levels and more steady plasma lithium levels in both B6129SF2/J (2-week oral treatment) and transgenic Tg2576 (8-week oral treatment) mice compared with Li2CO3. Oral administration of LISPRO for 28 weeks significantly reduced β-amyloid plaques and tau-phosphorylation. In addition, LISPRO significantly elevated pre-synaptic (synaptophysin) and post-synaptic protein (post synaptic density protein 95) expression in brains from transgenic 3XTg-AD mice. Taken together, our data suggest that LISPRO may be a superior form of lithium with improved safety and efficacy as a potential new disease modifying drug for AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Multi Target

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
beta Amyloid Load
Brain-Detergent Soluble beta Amyloid Peptide 40
Brain-Detergent Soluble beta Amyloid Peptide 42
Brain-Detergent Insoluble beta Amyloid Peptide 40
Brain-Detergent Insoluble beta Amyloid Peptide 42
Glycogen Synthase Kinase 3 beta (GSK3 beta)
Synaptic Proteins
Microtubule-Associated Protein 2 (MAP2)
Cyclooxygenase 2 (COX 2)
phospho-Glycogen Synthase Kinase 3 beta (phospho-GSK3 beta)
Total Tau Protein
Neuronal Loss
Synaptic Markers
Cell Biology
beta Amyloid Peptide Phagocytosis
CD40 Expression
Autophagic Markers
Neuronal Differentiation
Drug Concentration-Plasma
Drug Concentration-Brain
Brain/Plasma Ratio