Alzheimer Disease: Crawley JN

Crawley JN. · Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Porter Neuroscience Research, Center Building 35, Room 1C-903, Mail Code 3730, Bethesda, Maryland 20892-3730, USA. · Cell Mol Life Sci. · Pubmed #18500642 links to  free full text

Abstract: The neuropeptide galanin and its receptors are localized in brain pathways mediating learning and memory. Central microinjection of galanin impairs performance of a variety of cognitive tasks in rats. Transgenic mice overexpressing galanin display deficits in some learning and memory tests. The inhibitory role of galanin in cognitive processes, taken together with the overexpression of galanin in Alzheimer's disease, suggests that galanin antagonists may offer a novel therapeutic approach to treat memory loss in Alzheimer's patients.

Counts SE, Perez SE, Kahl U, Bartfai T, Bowser RP, Deecher DC, Mash DC, Crawley JN, Mufson EJ. · Department of Neurological Sciences, Rush-Presbyterian-St. Luke's Medical Center, 2242 West Harrison Street, Chicago, IL 60612, USA. · CNS Drug Rev. · Pubmed #11830760 No free full text.

Abstract: The neuropeptide galanin (GAL) is widely distributed in the mammalian CNS. Several lines of evidence suggest that GAL may play a critical role in cognitive processes such as memory and attention through an inhibitory modulation of cholinergic basal forebrain activity. Furthermore, GAL fibers hyperinnervate remaining cholinergic basal forebrain neurons in Alzheimer's disease (AD). This suggests that GAL activity impacts cholinergic dysfunction in advanced AD. Pharmacological and in vitro autoradiographic studies indicate the presence of heterogeneous populations of GAL receptor (GALR) sites in the basal forebrain which bind GAL with both high and low affinity. Interestingly, we have recently observed that GALR binding sites increase in the anterior basal forebrain in late-stage AD. Three G protein-coupled GALRs have been identified to date that signal through a diverse array of effector pathways in vitro, including adenylyl cyclase inhibition and phospholipase C activation. The repertoire and distribution of GALR expression in the basal forebrain remains unknown, as does the nature of GAL and GALR plasticity in the AD basal forebrain. Recently, GAL knockout and overexpressing transgenic mice have been generated to facilitate our understanding of GAL activity in basal forebrain function. GAL knockout mice result in fewer cholinergic basal forebrain neurons and memory deficits. On the other hand, mice overexpressing GAL display hyperinnervation of basal forebrain and memory deficits. These data highlight the need to explore further the putative mechanisms by which GAL signaling might be beneficial or deleterious for cholinergic cell survival and activity within basal forebrain. This information will be critical to understanding whether pharmacological manipulation of GALRs would be effective for the amelioration of cognitive deficits in AD.

Steiner RA, Hohmann JG, Holmes A, Wrenn CC, Cadd G, Juréus A, Clifton DK, Luo M, Gutshall M, Ma SY, Mufson EJ, Crawley JN. · Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195-7290, USA. · Proc Natl Acad Sci U S A. · Pubmed #11259657 links to  free full text

Abstract: Galanin is a neuropeptide with multiple inhibitory actions on neurotransmission and memory. In Alzheimer's disease (AD), increased galanin-containing fibers hyperinnervate cholinergic neurons within the basal forebrain in association with a decline in cognition. We generated transgenic mice (GAL-tg) that overexpress galanin under the control of the dopamine beta-hydroxylase promoter to study the neurochemical and behavioral sequelae of a mouse model of galanin overexpression in AD. Overexpression of galanin was associated with a reduction in the number of identifiable neurons producing acetylcholine in the horizontal limb of the diagonal band. Behavioral phenotyping indicated that GAL-tgs displayed normal general health and sensory and motor abilities; however, GAL-tg mice showed selective performance deficits on the Morris spatial navigational task and the social transmission of food preference olfactory memory test. These results suggest that elevated expression of galanin contributes to the neurochemical and cognitive impairments characteristic of AD.