Lewy bodies (LBs) are signature lesions of Parkinson's disease (PD), but LBs are not restricted to PD or to monoaminergic neurons in the brains of PD patients. For example, LBs are recognized increasingly throughout the cortex of patients with a late life dementia clinically similar to Alzheimer's disease (AD). The magnitude of the burden of cortical LBs in demented patients varies, but the detection of numerous cortical LBs in the postmortem brain defines a late life dementia as diffuse LB disease (DLBD) when there are no other diagnostic brain lesions. Alternatively, the co-existence of cortical LBs with classic AD lesions such as senile plaques (SPs) and neurofibrillary tangles (NFTs) in the brains of demented individuals is referred to as the LB variant of AD (LBVAD) or DLBD with AD. The recognition of LB dementias and the frequent co-occurrence of subcortical LBs in AD patients with or without extra-pyramidal signs has focused attention on the contributions of LBs to the dysfunction and death of cortical and subcortical neurons in AD and LB disorders. Although information on the biological consequences of LB formation in neurons is incomplete, the dominant structural components of these intra-neuronal inclusions are filaments. Accumulating evidence suggests that LB filaments are neurofilaments (NFs) composed of the high (NFH), middle (NFM) and low (NFL) molecular weight NF subunits. Since transgenic mice engineered to accumulate LB-like aggregates of perikaryal NFs show degenerative changes in affected neurons, the formation of NF-rich LBs may compromise the function of neurons and predispose them to premature death. For these reasons, this project is designed to develop a better understanding of the pathobiology of LBs by pursuing three major objectives: 1) Raising monoclonal antibodies (MAbs) to LBs purified from the brains of patients with DLBD or the LBVAD and using these MAbs to characterize NF and other proteins found in purified LBs as well as in cortical and subcortical LBs in situ in patients with PD, DLBD and the LBVAD; 2) Determining if neuronal mRNAs are depressed and if the integrity of axons and dendrites are compromised in cortical and subcortical neurons of patients with LBs disorders; 3) Characterizing the age related effects of the progressive accumulation of NF-rich LB-like lesions in mesencephalic and telencephalic neurons of transgenic mice engineered to express a NFH/LacZ fusion protein that causes aggregation of NFs into inclusions in neuronal perikarya. Taken together, these studies will yield novel insights into the biological consequences of LB formation in a transgenic mouse and in patients with PD, DLBD and the LBVAD.
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