Abstract: Midbrain dopamine (DA) neurons are susceptible to premature death in both PD and AD, but different populations of neurons are affected. As these populations of neurons provide input to different territories within the striatum there are different patterns of DA loss in the striatum. It is evident that different processes must be involved as LBs do not typically exist in midbrain neurons of AD cases. A significant proportion of AD cases also develop of extrapyramidal symptoms that closely resemble Parkinsonism in PD cases. It has been assumed that they must represent a combination of the two diseases (AD plus PD). However, it is also evident that AD patients developing extrapyramidal symptoms do not show the typical pathology of PD (i.e., accumulation of LBs and cell loss in the substantia nigra), yet show losses of DA transporter sites (DAT) associated with DA terminals within the striatum. Midbrain DA neurons show a complex organization of subgroups of neurons which can be differentiated into different populations based on morphological criteria, neuromelanin content, tyrosine hydroxylase (TH) content, DAT levels, DAT mRNA levels, TH mRNA levels, co-localized neuropeptides and their innervation by different striatonigral afferents. Finally, these populations of neurons provide input to different territories within the striatum and are affected in normal aging, PD and AD in distinctly different ways. Thus, it is unclear what role LBs play in either the vulnerability of midbrain DA neurons to premature death or in the neuronal disturbances within those neurons (e.g., reduced TH protein and TH mRNA). It has also not been identified how the biochemical heterogeneity of the different populations of midbrain DA neurons are related to these same processes. For these reasons this project is designed to characterize how LBs affect midbrain DA neurons by analysis of PD material with radioligand autoradiography, immunoautoradiography and in situ hybridization histochemistry for a variety of proteins and their mRNAs that are characteristic of midbrain DA neurons. Second characterize the age related biological consequences of the progressive accumulation of NF- rich LB-like lesion in midbrain DA neurons of transgenic mice engineered to express a NFH/LacZ fusion protein that causes aggregation of NF into inclusions in neuronal perkarrya. Third, identify if the biochemical heterogeneity of the different populations of midbrain DA neurons is related to neuronal vulnerability in AD and AD with Parkinsonism, since these diseases differ markedly in their susceptibility to DA neuron loss and pathogenesis to DA terminals. Fourth, determine by receptor autoradiography and in situ hybridization histochemistry if the target receptors (for members of the D2 receptor family) of these different populations of midbrain DA neurons are selectively affected in AD, PD and AD with Parkinsonism.