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

Yijun Pan, Jennifer L. Short, Stephanie A. Newman, Kwok H.C. Choy, Durgesh Tiwari, Christopher Yap, Danielle Senyschyn, William A. Banks, Joseph A. Nicolazzo

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)36-47
Number of pages12
JournalBrain, Behavior, and Immunity
Volume70
DOIs
Publication statusPublished - May 2018

Keywords

  • Alzheimer's disease
  • Beta-amyloid clearance
  • Blood–brain barrier
  • Cognitive function
  • Lithium
  • Low-density lipoprotein receptor-related protein 1

Cite this

@article{a6621d1241de4ce08bdd04ec5da01a7a,
title = "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",
author = "Yijun Pan and Short, {Jennifer L.} and Newman, {Stephanie A.} and Choy, {Kwok H.C.} and Durgesh Tiwari and Christopher Yap and Danielle Senyschyn and Banks, {William A.} and Nicolazzo, {Joseph A.}",
year = "2018",
month = "5",
doi = "10.1016/j.bbi.2018.03.007",
language = "English",
volume = "70",
pages = "36--47",
journal = "Brain, Behavior, and Immunity",
issn = "0889-1591",
publisher = "Mosby International",

}

Cognitive benefits of lithium chloride in APP/PS1 mice are associated with enhanced brain clearance of β-amyloid. / Pan, Yijun; Short, Jennifer L.; Newman, Stephanie A.; Choy, Kwok H.C.; Tiwari, Durgesh; Yap, Christopher; Senyschyn, Danielle; Banks, William A.; Nicolazzo, Joseph A.

In: Brain, Behavior, and Immunity, Vol. 70, 05.2018, p. 36-47.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Cognitive benefits of lithium chloride in APP/PS1 mice are associated with enhanced brain clearance of β-amyloid

AU - Pan, Yijun

AU - Short, Jennifer L.

AU - Newman, Stephanie A.

AU - Choy, Kwok H.C.

AU - Tiwari, Durgesh

AU - Yap, Christopher

AU - Senyschyn, Danielle

AU - Banks, William A.

AU - Nicolazzo, Joseph A.

PY - 2018/5

Y1 - 2018/5

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Beta-amyloid clearance

KW - Blood–brain barrier

KW - Cognitive function

KW - Lithium

KW - Low-density lipoprotein receptor-related protein 1

UR - http://www.scopus.com/inward/record.url?scp=85044039065&partnerID=8YFLogxK

U2 - 10.1016/j.bbi.2018.03.007

DO - 10.1016/j.bbi.2018.03.007

M3 - Article

VL - 70

SP - 36

EP - 47

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

SN - 0889-1591

ER -