Journal of Neurochemistry Lippincott—Raven Publishers, Philadelphia © 1997 International Society for Neurochernistry 1251-Galanin Binding Sites in Alzheimer’ s Disease: Increases in Hippocampal Subfields and a Decrease in the Caudate Nucleus *~Rafae1 RodrIguez-Puertas, *Siv Nilsson, tJulio Pascual, ~Ange1 Pazos, and *Tomas Hökfelt *Department of Neuroscience, Karolinska Institute, Stockholm, Sweden; and I-Unit of Pharmacology, Department of Physiology and Pharmacology, and ~Service of Neurology, Department of Medicine, University Hospital “Marques de Valdecilla,” University of Cantabria, Santander, Spain Abstract: Using iodinated human galanin and autoradi- ography, galanin binding sites were studied in cortical and hippocampal areas and in some brainstem nuclei in the brains of eight patients with senile dementia of the Alzheimer type (SDAT) and of nine matched control cases. The highest density of binding sites was found in the substantia nigra with a less intense labeling in the hippocampus and cortical regions. In the SDAT cases a significant increase in number of galanin binding sites was found in some hippocampal areas, a decrease in the caudate nucleus, and no significant changes in frontal and entorhinal cortices. These findings suggest that some central galanin systems may be deranged in SDAT. Key Words: 1251-Human galanin—Neuropeptides—Alzhei- mer’s disease—Human brain—Cholinergic system. J. Neurochem. 68, 1106—1113 (1997). The progressive decrement of memory and cognitive functions in the senile dementia of the Alzheimer type (SDAT) has been intimately associated with presynap- tic degeneration of cholinergic neurons in the nucleus basalis of Meynert (Geula and Mesulam, 1994). Based on these findings, a “cholinergic hypothesis” of de- mentia has been advanced, a model that associates SDAT with presynaptic degeneration, in a manner sim- ilar to the degeneration of nigrostriatal dopamine neu- rons known to occur in Parkinson’s disease. However, the marked neuronal degeneration occurring in SDAT is not associated with a selective loss of one specific neurotransmitter, but is characterized by deficits in multiple neurotransmitter systems, such as the seroto- nergic, noradrenergic, excitatory amino acid, and y- aminobutyric acid (GABA) systems (Fowler et al., 1992; Greenamyre and Maragos, 1993), suggesting that SDAT represents a more general disorder of neu- ronal communication. As some of these neurotransmitters have been cob- calized with neuropeptides, it is possible also that pep- tides may be affected in SDAT, as indicated in several studies (Gottfries et al., 1995). Of particular interest is galanin, a 29-amino-acid peptide originally isolated from the porcine intestine (Tatemoto et al., 1983). Early on it was found that a population of cholinergic forebrain neurons in the diagonal band nucleus of rat expresses galanin-like immunoreactivity (LI), but only after treatment with high doses of colchicine (Melander et al., 1985). Several studies have shown presence of galanin-LI in cholinergic forebrain neurons in primates, in fact, often at considerably higher levels in monkeys than in rats (Melander and Staines, 1986; Walker et al., 1989; Kordower and Mufson, 1990; Benzing et al., 1993; Evans et al., 1993), but, ac- cording to recent studies, galanin-LI is undetectable in apes and humans (Gentleman et al., 1989; Kowall and Beal, 1989; Kordower and Mufson, 1990; Walker et al., 1991; Benzing et al., 1993). Chan-Palay (1988a) reported a few galanin-immunoreactive neurons in the human basal forebrain nuclei and subsequently showed a galanin hyperinnervation of surviving neurons in the nucleus basalis of SDAT patients (Chan-Palay, 1988b), a finding that recently has been confirmed (Mufson et al., 1993). Using in situ hybridization Chan-Palay et al. (1990) described small and large neurons expressing galanin mRNA in human nucleus basalis of Meynert controls but mainly small neurons in the SDAT brains with a higher grain count per la- beled neuron in the Alzheimer’s disease brains. Beal et Received May 13, 1996; final revised manuscript received October 11, 1996; accepted October 18, 1996. Address correspondence and reprint requests to Dr. T. Hokfelt at Unit of Histology, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden. Abbreviations used: ChAT, choline acetyltransferase; LI, -like immunoreactivity; SDAT, senile dementia of the Alzheimer type. 1106