The role of nerve growth factor receptors (NGFR) in the development of Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by a progressive loss of cognitive ability and memories. An explanation for the loss of cholinergic basal forebrain (CBF) neurons in AD patients has long been under investigation; extensive research has focused on nerve growth factor (NGF) and its effects on these neurons.

Hefti et al. (1988) identified nerve growth factor receptors (NGFR) in cholinergic neurons of basal human forebrains. The use of a monoclonal antibody raised to recognize NGFR proteins allowed for the development of an immunohistochemical (IHC) procedure. The procedure was based off the co-localization of acetylcholinesterase (AChE) with NGFR and choline acetyltransferase (ChAT) expression. This allowed for the major cholinergic cell groups to be described in the basal forebrain: the medial septal nucleus (Ch1), the nucleus of the diagonal band of Broca (Ch2), and the nucleus basalis of Meynert (Ch4). The establishment that the IHC procedure was an effective means for visualizing cholinergic neurons allowed for the analysis of normal aged brains and those with AD. A decrease in immunoreactivity of NGFR were found in normal aged brains, however this decline was more noticeable in the brains of AD patients.

Mufson et al. 1989 did a qualitative analysis with the monoclonal antibodies that were previously described to be reliable by Hefti et al.  to further define NGFRs. This IHC procedure combined with bright- and dark-field microscopy allowed for the evaluation of brain sections of AD patients. Visualization revealed a pronounced loss of NGFR-immunoreactive neurons in the Ch4 subregions. Additionally, NGFR-containing fibers were found to be diminished in the fiber pathways of the Ch4 neurons. Furthermore, the regions Ch1 and Ch2 in AD brains were found to be less affected than the Ch4 region. A morphometric analysis of the immunoreactive neurons present in the Ch4 region allowed for a quantitative examination. The immunocytochemistry (ICC) revealed that the loss of NGFR-immunoreactive neurons is inversely correlated with the duration of AD.

Mufson et al. 1995 further investigated the Ch4 regions of AD patients with polyclonal antibodies raised against NGF and a monoclonal antibody against NGFR. Evaluation revealed an unequal ratio of NGFR to NGF in AD patients while the age-related controls exhibited a 1:1 relationship.  Specifically, a reduction in NGF immunoreactivity was found. Optical density morphometrics of the immunoreactive NGF neurons indicated diminished staining intensity.

In conclusion, Hefti et al.  described a creditable IHC procedure that gave consistent results for the identification of NGFRs in human brain sections. Their

findings suggest that there was a progressive degenerative effect on the cholinergic neurons in the basal forebrains with AD. Mufson et al. 1989 described that a combination of IHC and ICC procedures are a more informative analysis as ICC can elude to the loss neurons in specific regions of the brain.

Stating that previous findings described with a Nissl-staining method many have failed to include dystrophic neurons that fell below the defined perikaryal size. Their findings suggested that the Ch4 regions were the most affected in regard to NGFR-immunoreactive neurons, and that this loss is inversely correlated to the duration of the disease. Mufson et al. 1995 used a combination of the IHC procedure with optical density morphometrics to define a quantitative loss of staining intensity in NGF neurons in the Ch4 regions of AD brains. These findings led them to hypothesize that a defect in the retrograde transportation of NGF could be the result of insufficient utilization of trk receptors in AD patients.