Faculty Bibliography

The human cholinergic basal forebrain (CBF) is comprised of magnocellular hyperchromic neurons within the septal/diagonal band complex and nucleus basalis (NB) of Meynert. CBF neurons provide the major cholinergic innervation to the hippocampus, amygdala and neocortex. They play a role in cognition and attentional behaviors, and are dysfunctional in Alzheimer's disease (AD). The human CBF displays a continuum of large cells that contain various cholinergic markers, nerve growth factor (NGF) and its cognate receptors, calbindin, glutamate receptors, and the estrogen receptors, ERalpha and ERbeta. Admixed with these cholinergic neuronal phenotypes are smaller interneurons containing the m2 muscarinic acetylcholine receptor (mAChRs), NADPH-diaphorase, GABA, calcium binding proteins and several inhibitory neuropeptides including galanin (GAL), which is over expressed in AD. Studies using human autopsy material indicate an age-related dissociation of calbindin and the glutamate receptor GluR2 within CBF neurons, suggesting that these molecules act synergistically to induce excitotoxic cell death during aging, and possibly during AD. Choline acetyltrasnferease (ChAT) activity and CBF neuron number is preserved in the cholinergic basocortical system and up regulated in the septohippocampal system during prodromal as compared with end stage AD. In contrast, the number of CBF neurons containing NGF receptors is reduced early in the disease process suggesting a phenotypic silence and not a frank loss of neurons. In end stage AD, there is a selective reduction in trkA mRNA but not p75(NTR) in single CBF cells suggesting a neurotrophic defect throughout the progression of AD. These observations indicate the complexity of the chemoanatomy of the human CBF and suggest that multiple factors play different roles in its dysfunction in aging and AD.

Galanin (GAL) and GAL receptors (GALR) are overexpressed in limbic brain regions associated with cognition in Alzheimer disease (AD). The functional consequences of this overexpression are unclear. Because GAL inhibits cholinergic transmission and restricts long-term potentiation in the hippocampus, GAL overexpression may exacerbate clinical features of AD. In contrast, GAL expression increases in response to neuronal injury, and galaninergic hyperinnervation prevents the decreased production of protein phosphatase 1 subtype mRNAs in cholinergic basal forebrain neurons in AD. Thus, GAL may also be neuroprotective for AD. Further elucidation of GAL activity in selectively vulnerable brain regions will help gauge the therapeutic potential of GALR ligands for the treatment of AD

Age-related decline in dopamine receptor levels has been observed in regional studies of animal and human brains; however, identifying specific cellular substrates and/or alterations in distinct neuronal populations remains elusive. To evaluate whether age-related decreases in dopamine receptor subtypes are associated with specific cell populations in the hippocampus and entorhinal cortex, antisense RNA amplification was combined with cDNA array analysis to examine effects of aging on D1-D5 dopamine receptor mRNA expression levels in hippocampal CA1 pyramidal neurons and entorhinal cortex layer II stellate cells from post-mortem human brains (19-92 years). In CA1 pyramidal neurons, significant age-related decline was observed for dopamine receptor mRNAs (D1-D4, P < 0.001; D5, P < 0.05) but not for the cytoskeletal elements beta-actin, three-repeat (3R) tau, and four-repeat (4R) tau. In contrast, no significant changes were observed in stellate cells across the same cohort. Thus, senescence may be a factor responsible for cell-specific decrements in dopamine receptor gene expression in one population of neurons within a circuit that is critical for learning and memory. Furthermore, these results support the hypothesis that alterations in dopaminergic function may also be related to behavioral abnormalities, such as psychosis, that occur with aging.