Galanin expression within the basal forebrain in Alzheimer\u27s disease: Comments on therapeutic potential

The inhibitory neuropeptide galanin has widespread distribution throughout the central nervous system. Studies indicate that galanin modulates cognition by regulating cholinergic basal forebrain (CBF) neuron function. The chemoanatomic organization of galanin within the mammalian CBF differs across species. In monkeys, all CBF neurons coexpress galanin, whereas in apes and humans galanin is found within a separate population of interneurons that are in close apposition to the CBF perikarya. Pharmacologic investigations revealed a low and high affinity galanin receptor within the basal forebrain in humans. In vitro autoradiographic investigations of the primate brain indicate that galanin receptors are concentrated within the anterior subfields of the CBF as well as the bed nucleus of the stria terminalis, amygdala, and entorhinal cortex. Galaninergic fibers hyperinnervate remaining CBF neurons in Alzheimer\u27s disease. Because galanin inhibits the release of acetylcholine in the hippocampus, it has been suggested that the overexpression of galanin in Alzheimer\u27s disease may downregulate the production of acetylcholine within CBF perikarya, further exacerbating cholinergic cellular dysfunction in this disorder. These observations suggest that the development of a potent galanin antagonist would be a useful step towards the successful pharmacologic treatment of Alzheimer\u27s disease

Galanin: Neurobiologic mechanisms and therapeutic potential for Alzheimer\u27s disease

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\u27s 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 latestage 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

Galanin Expression within the Basal Forebrain in Alzheimer's Disease: Comments on Therapeutic Potentiala

The inhibitory neuropeptide galanin has widespread distribution throughout the central nervous system. Studies indicate that galanin modulates cognition by regulating cholinergic basal forebrain (CBF) neuron function. The chemoanatomic organization of galanin within the mammalian CBF differs across species. In monkeys, all CBF neurons coexpress galanin, whereas in apes and humans galanin is found within a separate population of interneurons that are in close apposition to the CBF perikarya. Pharmacologic investigations revealed a low and high affinity galanin receptor within the basal forebrain in humans. In vitro autoradiographic investigations of the primate brain indicate that galanin receptors are concentrated within the anterior subfields of the CBF as well as the bed nucleus of the stria terminalis, amygdala, and entorhinal cortex. Galaninergic fibers hyperinnervate remaining CBF neurons in Alzheimer\u27s disease. Because galanin inhibits the release of acetylcholine in the hippocampus, it has been suggested that the overexpression of galanin in Alzheimer\u27s disease may downregulate the production of acetylcholine within CBF perikarya, further exacerbating cholinergic cellular dysfunction in this disorder. These observations suggest that the development of a potent galanin antagonist would be a useful step towards the successful pharmacologic treatment of Alzheimer\u27s disease