One of the most consistent pathological features in Alzheimer's disease (AD) is a cortical cholinergic hypofunction which results from degeneration of cholinergic neurons located within the basal forebrain. The cholinergic deficit occurs early in the disease process and correlates with disease severity and duration. Additionally, there is a large experimental and clinical literature demonstrating that the cholinergic basal forebrain system is involved in normal and pathological memory processes. These data indicate the contribution of this system tot eh major symptomatology of AD. Converging lines of evidence indicate that the development and maintenance of cholinergic basal forebrain neurons is dependent upon the trophic factor nerve growth factor (NGF). Based upon these data, it was suggested that impaired NGF trophism underlies the degeneration of basal forebrain neurons in AD. Initial studies demonstrating normal NGF synthesis and expression of its low affinity NGF receptor in AD diminished enthusiasm for this view. However, NGF trophism occurs through a series of molecular events. We have recently demonstrated that NGF transport mechanisms are defective in AD and hypothesize this event may mediate the degenerative events seen in the AD basal forebrain. In AD, we found a reduced expression of NGF- immunoreactivity within the cholinergic basal forebrain and an accumulation of NGF within the cerebral cortex. In the present series of studies.
Specific Aims 1 and 2 will establish the extent to which diminished NGF- immunoreactivity within the basal forebrain and accumulated NGF protein within the cerebral cortex is associated with the clinical progression of AD. Well characterized patients with mild, moderate, and severe dementia will be compared to age-matched controls. The immunohistochemical expression of NGF within the basal forebrain and NGF protein within different regions of the cerebral cortex will be quantified and compared between patient populations.
Specific Aims 3 will utilize the fact that subfields of the cholinergic basal forebrain are selectively vulnerable in AD to assess the degree to which reduced transported NGF is associated specifically with neural degeneration. NGF-immunoreactivity will be quantified and the expression of NGF-ir will be compared between cholinergic septal.diagonal neurons which are sustained in AD and neurons of the nucleus basalis which extensively degenerate in AD.
Specific Aim 4 will focus upon the mechanisms responsible for the diminished NGF- immunoreactivity in the basal forebrain and accumulated NGF protein within the cortex in AD. We hypothesize that these events are due to an impairment in the high affinity trkA receptor. This is the receptor which transduces the NGF signal. In situ hybridization will be used to determine whether trkA mRNA is altered in AD as a function of disease progression. These studies will help establish the role of impaired NGF trophism in CBF degeneration and the progression of clinical dementia in AD. The data derived from these studies will be integrated with others in the program project which are also investigating radiologic and pathologic parameters of disease progression in AD.
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