INTR10

Authors:

Mufson EJ

Institutions:

Rush University Medical Center

Title of abstract : Cholinotrophic Dysfunction in During the Progression of Alzheimer’s Disease

Abstract text:

The cholinergic cortical projection system requires the interaction of nerve growth factor (NGF) and it high (trkA) and low (p75NTR) affinity receptors for biological activity and is neurotrophic dependent neural axis is vulnerable in Alzheimer’s disease (AD). The molecular mechanisms underlying this vulnerability during the progression of AD remain unknown. To determine the molecular pathologenesis of this cholinotropic system, we evaluated postmortem tissue from subjects clinically categorized with no cognitive impairment (NCI), mild cognitive impairment (MCI) or AD. The number of chloline acetyltransferase (ChAT)-positive neurons was unchanged in MCI and mild AD, while the number of neurons immunopositive for the NGF receptors trkA and p75NTR was significantly reduced compared to NCI, supporting a phenotypic rather than frank cholinergic neuronal degeneration in MCI. Gene expression profile analysis of single cholinergic neurons revealed that trkA mRNA was decreased in MCI and correlated with cognitive decline, suggesting a trafficking defect and that this may be an early biomarker for AD. Moreover, there is an accumulation of proNGF in cholinergic basal forebrain (CBF) cortical target sites. Single cell gene profiling revealed no significant differences in expression levels for the six- tau isoforms across groups within CBF neurons. However, a significant decrease in the 3Rtau/4Rtau expression ratio was found in MCI and AD relative to NCI suggesting that neurotrophic changes may play a role in the development of neurofibrillary tangles in CBF neurons. Taken together, these cholinotrophic CBF molecular studies suggest that people with MCI are already in the early stages of AD. A recent phase 1 clinical trial of NGF intraparenchymal gene therapy has shown promising results with no adverse affects and indications that this treatment may even slow the course of AD.

This entry was posted on Tuesday, July 22nd, 2008 at 13:10 and is filed under AD: memory and aging, all. You can follow any responses to this entry through the RSS 2.0 feed. Responses are currently closed, but you can trackback from your own site.