Details

Autor(en) / Beteiligte

• Christie, Richard H

Titel

In vivo imaging of amyloid deposition in a transgenic mouse model of Alzheimer's disease

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2001

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Alzheimer's disease (AD) is an inherently kinetic process, evolving clinically from barely perceptible functional deficits to severe memory loss and cognitive incapacity within a span of several years. One of the neuropathological hallmarks of the disease is the accumulation of extracellular senile plaques, deposits of Aβ, a 40–42 amino acid peptide derived from the amyloid precursor protein (APP). Previous in vitro work has suggested that Aβ is insoluble, and precipitates to form aggregates; deposition of exogenous Aβ enlarges pre-existing plaques according to first-order kinetics and in a reversible manner. Transgenic mice expressing a mutant form of human APP develop amyloid deposits similar to those seen in AD. Observation of the formation or growth of individual plaques in these mice is beyond the reach of in vivo imaging technologies such as MRI or CAT scans. The present work applies a new imaging technology, two-photon laser scanning microscopy (TPLSM), to the in vivo visualization of amyloid deposition in these animals. A method is described for the visualization of thioS-positive plaque cores in the brain of living transgenic mice, and the re-imaging of the same cores in the same animal days or weeks later. Analysis of thioS-positive cores over time periods as long as 5 months reveals a remarkable in vivo stability. Core morphology remains unchanged over all time intervals examined, and core size measurements remain constant to within the variability of the measurement system. These data argue for a model of plaque core formation by rapid precipitation of stable aggregates rather than continual deposition of peptide onto a preformed template. ThioS-positive cores remain stable chronic lesions for the remainder of the animal's lifetime, and represent a stable target for the testing of anti-amyloid pharmaceuticals. These transgenic mice also accumulate amyloid around cortical and leptomeningeal vessels starting at about 10 months of age. This accumulation is similar to the human amyloid angiopathy that leads to loss of smooth muscle cells (SMCs), weakening of the vessel wall, and hemorrhage in some clinical cases. Data from mice expressing APP, but without overt amyloid deposition, suggest an effect of soluble APP on vessel response to vasodilators. The present work examines the effect of amyloid deposition on vascular structure and function. Amyloid deposition on pial vessels is initially accompanied by physical disruption of SMCs, separating them, but without causing cell loss. By 24 months of age, however, over half the SMCs are lost within regions of vessels affected with amyloid deposition. To examine whether the disruption of SMCs in young animals would interfere with vessel function, vessel response to vasodilators was measured in 14-month-old animals with moderate amyloid deposition, as well as younger animals with no amyloid deposition. Endothelium-dependent and endothelium-independent vasodilators were applied in a cranial window preparation; response to both was impaired in amyloid-laden vessels as compared to vessels in young transgenics and non-transgenic controls. These data argue for a toxic effect of deposited amyloid on the SMCs in the vessel wall which interferes with SMC physiology prior to causing cell death. This impairment of vessel function would result in an inability of the vessel to autoregulate in response to normal physiologic stimuli, and may be clinically significant.