Biomedical subjects

Karen F S Bell

Publications and source records attributed to Karen F S Bell.

3 recordsLinked to original sources

PubMed2006

ADAM-10 over-expression increases cortical synaptogenesis.

Cortical cholinergic, glutamatergic and GABAergic terminals become upregulated during early stages of the transgenic amyloid pathology. Abundant evidence suggests that sAPP alpha, the product of the non-amyloidogenic alpha-secretase pathway, is neurotrophic both in vitro and when exogenously applied in vivo. The disintegrin metalloprotease ADAM-10 has been shown to have alpha-secretase activity in vivo. To determine whether sAPP alpha has an endogenous biological influence on cortical presynaptic boutons in vivo, we quantified cortical cholinergic, glutamatergic and GABAergic presynaptic bouton densities in either ADAM-10 moderate expressing (ADAM-10 mo) transgenic mice, which moderately overexpress ADAM-10, or age-matched non-transgenic controls. Both early and late ontogenic time points were investigated. ADAM-10 mo transgenic mice display significantly elevated cortical cholinergic, glutamatergic and GABAergic presynaptic bouton densities at the early time point (8 months). Only the cholinergic presynaptic bouton density remains significantly elevated in late-staged ADAM-10 mo transgenic animals (18 months). To confirm that the observed elevations were due to increased levels of endogenous murine sAPP alpha, exogenous human sAPP alpha was infused into the cortex of non-transgenic control animals for 1 week. Exogenous infusion of sAPP alpha led to significant elevations in the cholinergic, glutamatergic and GABAergic cortical presynaptic bouton populations. These results are the first to demonstrate an in vivo influence of ADAM-10 on neurotransmitter-specific cortical synaptic plasticity and further confirm the neurotrophic influence of sAPP alpha on cortical synaptogenesis.

ADAM Proteins↗

PubMed2006

Altered synaptic function in Alzheimer's disease.

Alzheimer's disease is the leading cause of dementia in the elderly, presenting itself clinically by progressive loss of memory and learning. Since synaptic density correlates more closely with cognitive impairment than any other pathological lesion observable in the disease pathology, an increased understanding of the mechanisms behind synaptic disconnection is of vital importance. Our lab investigated the neurotransmitter-specific status of distinct cortical presynaptic bouton populations in various transgenic mouse models of the Alzheimer's-like amyloid pathology in order to assess their involvement throughout the progression of the pathology. These studies have revealed that the amyloid pathology appears to progress in a neurotransmitter-specific manner where the cholinergic terminals appear most vulnerable, followed by the glutamatergic terminals and finally by the somewhat more resilient GABAergic terminals. This review will discuss additional studies which also provide evidence of a neurotransmitter-specific pathology as well as comment on the potential explanations for the observed vulnerabilities, touching upon metabolic demand, trophic support and receptor mediated activation.

Alzheimer Disease↗

PubMed2005

The amyloid pathology progresses in a neurotransmitter-specific manner.

Past studies using transgenic models of early-staged amyloid pathology, have suggested that the amyloid pathology progresses in a neurotransmitter-specific manner where cholinergic terminals appear most vulnerable, followed by glutamatergic terminals and finally by somewhat more resistant GABAergic terminals. To determine whether this neurotransmitter-specific progression persists at later pathological stages, presynaptic bouton densities, and the areas of occupation and localization of plaque adjacent dystrophic neurites were quantified in 18-month-old APP(K670N, M671L)+PS1(M146L) doubly transgenic mice. Quantification revealed that transgenic animals had significantly lower cholinergic, glutamatergic and GABAergic presynaptic bouton densities. Cholinergic and glutamatergic dystrophic neurites appear to be heavily influenced by fibrillar Abeta as both types displayed a decreasing area of occupation with respect to increasing plaque size. Furthermore, cholinergic dystrophic neurites reside in closer proximity to plaques than glutamatergic dystrophic neurites, while GABAergic dystrophic neurites were minimal regardless of plaque size. To investigate whether similarities exist in the human AD pathology, a monoclonal antibody (McKA1) against the human vesicular glutamate transporter 1 (VGluT1) was developed. Subsequent staining in AD brain tissue revealed the novel presence of glutamatergic dystrophic neurites, to our knowledge the first evidence of a structural glutamatergic deficit in the AD pathology.

Acetylcholine↗