Ling Y. Munsell

Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease

Alzheimer’s disease is associated with reduced β-amyloid clearance from the brain Alzheimer’s disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of disease-modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer’s disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of participants with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer’s disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production rates. Thus, the common late-onset form of Alzheimer’s disease is characterized by an overall impairment in Aβ clearance.

Decreased clearance of CNS beta-amyloid in Alzheimer's disease.

Alzheimer’s disease is associated with reduced β-amyloid clearance from the brain Alzheimer’s disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of disease-modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer’s disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of participants with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer’s disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production rates. Thus, the common late-onset form of Alzheimer’s disease is characterized by an overall impairment in Aβ clearance.

Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo.

Certain disease states are characterized by disturbances in production, accumulation or clearance of protein. In Alzheimer disease, accumulation of amyloid-β (Aβ) in the brain and disease-causing mutations in amyloid precursor protein or in enzymes that produce Aβ indicate dysregulation of production or clearance of Aβ. Whether dysregulation of Aβ synthesis or clearance causes the most common form of Alzheimer disease (sporadic, >99% of cases), however, is not known. Here, we describe a method to determine the production and clearance rates of proteins within the human central nervous system (CNS). We report the first measurements of the fractional production and clearance rates of Aβ in vivo in the human CNS to be 7.6% per hour and 8.3% per hour, respectively. This method may be used to search for novel biomarkers of disease, to assess underlying differences in protein metabolism that contribute to disease and to evaluate treatments in terms of their pharmacodynamic effects on proposed disease-causing pathways.

Effects of Systemically Administered Lithium on Phosphoinositide Metabolism in Rat Brain, Kidney, and Testis

Abstract: A single subcutaneous dose of 10 mEq/kg LiCl gives rise to an increase in the cerebral cortex level of myo‐inositol‐1‐P (I1P) that closely follows cortical lithium levels and, at maximum, is 40‐fold above the control value. Kidney and testis show smaller increases in I1P level following LiCl administration. The I1P level is still sixfold greater than that of untreated rat cortex 72 h later. In cortex, parallel increases also occur in myo‐inositol‐4‐P (I4P) and myo‐inositol 1,2‐cyclic‐P (cI1, 2P), whereas myo‐inositol‐5‐P (I5P) remains unchanged. The cortical increases in I1P and I4P levels are partially reversed by administering 150 mg/kg of atropine 22 h after the LiCl, treatment that does not affect cI1, 2P. When doses of LiCl from 2 to 17 mEq/kg are given, the cerebral cortex levels of I1P and myo‐inositol, measured 24 h later, are found to reach a plateau at about 9 mEq/kg of LiCl, whereas cortical lithium levels continued to increase with greater LiCl doses. Levels of ail three of the brain phosphoinositides are unchanged by the 10 mEq/kg LiCl dose, as is the uptake of 32Pi into these lipids. Chronic dietary administration of LiCl for 22 days showed that the effects of lithium on I1P and myo‐inositol levels persist for that period. Over the course of the chronic administration of the lithium, levels of I1P, myo‐inositol, and of lithium in cortex remained significantly correlated. We believe that these increases in inositol phosphates result from endogenous phosphoinositide metabolism in cerebral cortex and that lithium is capable of modulating that metabolism by reducing cellular myo‐inositol levels. The size of the effect is a function of both lithium dose and the degree of stimulation of receptor‐linked phosphoinositide metabolism. This property of lithium may explain part of its ability to moderate the symptoms of mania. Our chronic study suggests that prolonged administration of LiCl does not resuit in compensatory changes in myo‐inositol‐1‐P synthase or myo‐inositol‐1‐phosphatase.

Decreased Clearance of CNS Amyloid-β in Alzheimer’s Disease

Alzheimer’s disease is associated with reduced β-amyloid clearance from the brain Alzheimer’s disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of disease-modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer’s disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of participants with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer’s disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production rates. Thus, the common late-onset form of Alzheimer’s disease is characterized by an overall impairment in Aβ clearance.

Amyloid-β efflux from the central nervous system into the plasma.

The aim of this study was to measure the flux of amyloid‐β (Aβ) across the human cerebral capillary bed to determine whether transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS).

Detection of Receptor-Linked Phosphoinositide Metabolism in Brain of Lithium-Treated Rats

The metabolism of phosphoinositides that results from receptor-coupled processes in the CNS can be readily detected in rats treated with low doses of lithium chloride. Brain levels of myo-inositol 1-phosphate (IP) rise in response to agonists of this class of receptor and decrease on treatment with antagonists. For example, peripheral administration of the direct-acting muscarinic cholinergic agonist pilocarpine causes a rapid (<30 min) increase in the IP levels of cerebral cortex. Subsequent administration of the muscarinic antagonist atropine reverses the effect. The anticholinesterase physostigmine produces a similar IP elevation. Both of these agents produce seizures when given to lithium-treated rats. Because diazepam reduces the increase in IP while arresting seizures and because peripherally-administered kainic acid causes both seizures and an elevation in IP level that is partially reversed by atropine, we believe that the seizure activity itself contributes to the increase in IP observed. Nicotine, when administered subcutaneously to the lithium-treated rat, suppresses IP levels, while the two nicotinic cholinergic ganglionic blockers mecamylamine and pempidine give rise to atropine-reversible increases in IP that are comparable to the increases obtained with muscarinic agonists but without producing seizures. The effect of the nicotinic blockers is ascribed to disinhibition of Renshaw cell-like circuits.

Differential Uptake of Lithium Isotopes by Rat Cerebral Cortex and Its Effect on Inositol Phosphate Metabolism

Abstract: Twenty hours following the subcutaneous administration of 5 mEq/kg doses of 6LiCl and 7LiCl to two groups of rats, the cerebral cortex molar ratio of 6Li+/7Li+ is 1.5. The effects of the lithium isotopes on cortex myo‐inositol and myo‐inositol‐1 ‐phosphate levels are the same as we have reported earlier: a Li+ concentration‐dependent lowering of myo‐inositol and increase in myo‐inositol‐1‐phosphate. Thus 6LiCl, when administered at the same dose as 7LiCl, produces the larger effect on inositol metabolism. When the 6LiCl and 7LiCl doses were adjusted to 5 mEq/kg and 7 mEq/kg, respectively, the cortical lithium myo‐inositol and myo‐inositol‐1‐phosphate levels of each group of animals became approximately equal, suggesting that the isotope effect occurs at the level of tissue uptake, but not on inositol phosphate metabolism. The inhibition of myo‐inositol‐1‐phosphatase by the two lithium isotopes in vitro showed no differential effect. The isotope effect on cerebral cortex uptake of lithium is in the same direction as that reported by others for erythrocytes and for the CSF/plasma ratio, but of larger magnitude.

Amyloid-β efflux from the CNS into the plasma

The aim of this study was to measure the flux of amyloid‐β (Aβ) across the human cerebral capillary bed to determine whether transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS).

Amyloid-β efflux from the central nervous system into the plasma: Brain Efflux of Amyloid-β

The aim of this study was to measure the flux of amyloid‐β (Aβ) across the human cerebral capillary bed to determine whether transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS).