Cognitive benefits of lithium chloride in APP/PS1 mice are associated with enhanced brain clearance of β-amyloid

Abstract

Epidemiological evidence suggests that people with bipolar disorder prescribed lithium exhibit a lower risk of Alzheimer's disease (AD) relative to those prescribed other mood-stabilizing medicines. Lithium chloride (LiCl) reduces brain β-amyloid (Aβ) levels, and the brain clearance of Aβ is reduced in AD. Therefore, the purpose of this study was to assess whether the cognitive benefits of LiCl are associated with enhanced brain clearance of exogenously-administered Aβ. The brain clearance of intracerebroventricularly (icv) administered ¹²⁵I-Aβ₄₂ was assessed in male Swiss outbred mice administered daily oral NaCl or LiCl (300 mg/kg for 21 days). LiCl exhibited a 31% increase in the brain clearance of ¹²⁵I-Aβ₄₂ over 10 min, which was associated with a 1.6-fold increase in brain microvascular expression of the blood-brain barrier efflux transporter low density lipoprotein receptor-related protein 1 (LRP1) and increased cerebrospinal fluid (CSF) bulk-flow. 8-month-old female wild type (WT) and APP/PS1 mice were also administered daily NaCl or LiCl for 21 days, which was followed by cognitive assessment by novel object recognition and water maze, and measurement of soluble Aβ₄₂, plaque-associated Aβ₄₂, and brain efflux of ¹²⁵I-Aβ₄₂. LiCl treatment restored the long-term spatial memory deficit observed in APP/PS1 mice as assessed by the water maze (back to similar levels of escape latency as WT mice), but the short-term memory deficit remained unaffected by LiCl treatment. While LiCl did not affect plaque-associated Aβ₄₂, soluble Aβ₄₂ levels were reduced by 49.9% in APP/PS1 mice receiving LiCl. The brain clearance of ¹²⁵I-Aβ₄₂ decreased by 27.8% in APP/PS1 mice, relative to WT mice, however, LiCl treatment restored brain ¹²⁵I-Aβ₄₂ clearance in APP/PS1 mice to a rate similar to that observed in WT mice. These findings suggest that the cognitive benefits and brain Aβ₄₂ lowering effects of LiCl are associated with enhanced brain clearance of Aβ₄₂, possibly via brain microvascular LRP1 upregulation and increased CSF bulk-flow, identifying a novel mechanism of protection by LiCl for the treatment of AD.

Keywords: Alzheimer’s disease; Beta-amyloid clearance; Blood–brain barrier; Cognitive function; Lithium; Low-density lipoprotein receptor-related protein 1.