A crucial challenge in dementia research today is tounderstand the neurobiologic mechanisms underlying the degenerative and regenerative events which occur during the progression of Alzheimer's disease (AD). This PPG component will examine a set of hypotheses aimed at gaining greater insight into the galaninergic neural remodeling response associated with the survival of cholinergic basal forebrain (CBF) neurons in AD. Recent findings have led us to hypothesize that increased GAL may be neuroprotective for select CBF neurons since neural degeneration is least in the anterior CBF where GAL remodeling occurs, the loss of CBF neurons is minimal in people with mild cognitive impairment (MCI) and mild AD (50) at a point in the disease process where GAL remodeling begins (see Preliminary data), there is a 35% reduction in CBF neurons in the anterior CBF in mice lacking the GAL gene, GAL enhances neurite outgrowth in cultured sensory neurons and GAL and GAL receptors are expressed in embryonic stem cells suggesting a role in cell differentiation. The present application tests a series of hypotheses that during the transition from MCI to AD that 1) GAL remodeling enhances the expression of genes associated with neuroprotection,in anterior CBF neurons including nerve growth factor and its receptors and specific GAL receptor genes; 2) Selectively stabilizes the expression of genes associated with micortublular formation in CBF neurons containing site-specific tau phosphorylation epitopes using antibodies against site-specific tau phosphopeptides provided by Dr. Binder (Project 4); 3) GAL remodeling is associated with an increase in the number of GAL mRNA expressing neurons as AD progresses or alternatively there is an increase in GAL mRNA synthesis per anterior CBF neuron during disease progression, 4; There is an increase in GAL synaptic-like appositions upon anterior CBF hyper innervated neurons using a confocal microscope. GAL remodeling will be evaluated in individuals derived from the Rush Religious Orders Study with a clinical diagnosis of no cognitive impairment, MCI, and AD. The molecular findings will becorrelated with cognitive (i.e., declarative, working and episodic memory), attention tests, pathology (i.e., Braak and Reagan Criteria, plaque load) and diagnostic categories. These investigations will lead to novel pharmacological treatments aimed at slowing the relentless onslaught of AD. Summary of the Project 3 Discussion: The revised application is seen as an improvement. There is a consensus that the reviewers recognized the work of Project 3 remains correlative, since no mechanistic investigations are planned; indeed, they may not even be possible when limiting the plan to study of human patient material.
Aim 1 was viewed as the most interesting aspect of Project 3.
For Aim 2, reviewers strongly urged the PL to include the development of probes to the three galanin receptors for use in the in situ hybridization studies. The sequences are known such that oligonucleotide probes can be as easily prepared as the plan for development of probes for galanin mRNA. A good deal of valuable information could be derived from their use.
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