Project: Research project

Project Details


In Alzheimer's disease (AD), there are striking changes in the distribution
of choline acetyltransferase (ChAT) and the various molecular forms of
acetylcholinesterase (AChE) in the cerebral cortex and nucleus basalis of
Meynert (nbM). Our provisional working hypothesis is that these changes
are due primarily to altered axonal transport in diseased cholinergic
neurons. The major emphasis is on the acquisition of secure information on
ChAT, AChE, and the corresponding mRNAs within individual cholinergic
neurons and on the development of a system capable of generating similar
information on many other proteins and mRNAs. We propose to evaluate the
effect of aging and AD on ChAT and the varius molecular forms of AChE (a)
on a per neuron basis in cholinergic nbM neurons, (b) at stereotyped
locations along the course of cholinergic axons projecting from the nbM,
(c) on a per axon basis in cholinergic axons of the fornix, and (d) in
cerebral cortex and hippocampus. The effect of aging and AD on ChAT are
AChE mRNA in cholinergic nbM neurons will also be evaluated on a per neuron
basis. If normal aging causes changes qualitatively similar to those in
AD, one may be able to gain considerable insight into the initiating events
and the progression of the neuronal pathology in AD by carefully examining
non-demented individuals in appropriate age groups. It is primarily for
this reason that examination of the effect of aging is proposed. We plan
to evaluate the effect of the many drugs that alter fast and/or slow axonal
transport on ChAT and the various molecular forms of AChE in cultured PC12
cells. The goal is (a) to support our working hypothesis that impaired
axonal transport plays an important role in the neuronal pathology of AD by
demonstrating that appropriate impairment of axonal transport causes
changed in ChAT and AChE like those observed in AD, and (b) to determine
whether changes like those seen in AD occur only after specific
perturbations of transport or develop non-specifically. The altered
distribution of ChAT and AChE caused by axonal transport inhibitors could
result from associated changes in any of the processes that regulate the
level of these proteins. To assess this issue, the synthesis, assembly,
secretion, and degradation of the various molecular forms of AChE will be
assessed in drug-treated and control PC12 cells using techniques previously
developed in this laboratory.
Effective start/end date12/1/865/31/13


  • Medicine(all)