Elsevier

Brain Research

Volume 1085, Issue 1, 26 April 2006, Pages 183-188
Brain Research

Research Report
Alzheimer's disease drugs promote neurogenesis

https://doi.org/10.1016/j.brainres.2006.02.081Get rights and content

Abstract

Alzheimer's disease (AD) is associated with increased production of new neurons (neurogenesis), which may be directed at brain repair. However, the effect of drugs used to treat AD on neurogenesis is unknown. We administered tacrine, galantamine or memantine to mouse cerebral cortical cultures in vitro, and to mice in vivo, and measured neurogenesis by labeling newborn cells with bromodeoxyuridine (BrdU) and confirming their neuronal lineage by cell-type-specific protein expression. All three drugs increased BrdU incorporation into cortical cultures in vitro by up to 40%, and increased BrdU labeling of cells in neuroproliferative regions of the adult mouse brain in vivo by 26–45%. BrdU labeling was associated with neuronal markers, such as Hu and βIII tubulin. Thus, drugs used to treat AD increase cerebral neurogenesis both in vitro and in vivo, which may contribute to their therapeutic effects.

Introduction

Because current treatment for most neurodegenerative diseases is severely limited, interest has arisen in the prospect of cell replacement therapy, based on evidence that neurogenesis, or the production of new neurons, continues in the adult brain. Adult neurogenesis is subject to physiological regulation by glucocorticoids, sex hormones, growth factors, neurotransmitters, learning and stress (Cameron et al., 1998) and can be modified by clinically used drugs, including lithium, antidepressants, phosphodiesterase inhibitors, anti-inflammatory drugs and statins (Chen et al., 2000, Chen et al., 2003, Santarelli et al., 2003, Zhang et al., 2002).

Alzheimer's disease (AD) may be an appropriate condition in which to consider cell replacement therapy. We found recently that neurogenesis is increased in the hippocampus of patients with AD (Jin et al., 2004b) and in transgenic mice that express an amyloid precursor protein mutation found in some familial AD pedigrees (Jin et al., 2004a), which may reflect a cerebral response directed towards self-repair. If neurons produced by adult neurogenesis can replace cells that are lost through disease, then measures to stimulate neurogenesis might benefit patients with AD.

Two classes of drugs are the current mainstays of AD therapy. Acetylcholinesterase (AChE) inhibitors like tacrine, donepezil, galantamine and rivastigmine produce modest improvement in cognitive and behavioral symptoms (Kawas, 2003, Mayeux and Sano, 1999, Scarpini et al., 2003). Their effects could conceivably include stimulation of neurogenesis because cholinergic receptors are expressed on neuronal progenitors and are coupled to cell proliferation (Atluri et al., 2001, Li et al., 2001, Ma et al., 2000, Williams et al., 2004). Memantine, an N-methyl-d-aspartate (NMDA)-preferring glutamate receptor antagonist was recently introduced for treatment of AD (Reisberg et al., 2003, Tariot et al., 2004). Memantine might also operate partly through induction of neurogenesis because other NMDA antagonists have this property (Bernabeu and Sharp, 2000, Cameron et al., 1995, Nacher et al., 2003, Nacher et al., 2001).

To investigate the possible effects of drugs used to treat AD on neurogenesis, we administered these drugs to mouse cerebral cortical cell cultures in vitro and to mice in vivo and measured neurogenesis by labeling newborn cells with bromodeoxyuridine (BrdU) and confirming their neuronal lineage using cell-type-specific protein markers. Our results indicate that drugs commonly used to treat AD stimulate neurogenesis and raise the possibility that this might contribute to their therapeutic effects.

Section snippets

In vitro studies

First, we examined the effect of AD drugs on BrdU incorporation into cortical cultures in vitro. As reported previously (Jin et al., 2002b), ∼80% of cells in these cultures expressed markers of immature cells of neuronal lineage, including Hu (Fig. 1a) and βIII tubulin, whereas astroglial, microglial or endothelial markers were detected on <2% of cells. We studied tacrine, a selective and reversible AChE inhibitor; galantamine, which has a similar effect, but also allosterically enhances

Discussion

The major finding reported here is that drugs used to treat cognitive impairment in AD, including both AChE inhibitors and an NMDA antagonist, also potentiate neurogenesis in the two principal neuroproliferative regions of the rodent brain—the SGZ of the hippocampal DG and the forebrain SVZ. Drug-induced enhancement of neurogenesis was observed both in neuronal cultures and in vivo, suggesting that the drugs involved stimulate cell-autonomous responses that do not depend on non-neuronal cell

Materials

BrdU, tacrine and galantamine were purchased from Sigma (St. Louis, MO), and memantine hydrochloride (Ebixa®) was from H. Lundbeck A/S, Valby, Denmark.

Animals

Experiments were carried out in accordance with the NIH Guide for the Care and Use of Laboratory Animals, and all efforts were made to minimize suffering, reduce the number of animals used and employ alternatives to animals where available. Euthanasia was produced by inhalation of 70–100% carbon dioxide followed by decapitation.

In vitro studies

Primary neuronal

Acknowledgments

Supported by NIH grants AG21980 to K.J. and NS44921 to D.A.G.

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