AB deposition and related pathology in an APP x PS1 transgenic mouse model of Alzheimer s disease

Abstract

Summary. A transgenic mouse bearing mutant transgenes linked to familial forms of Alzheimer’s disease (AD) for the amyloid precursor protein and presenilin-1 (TASTPM) showed Aß plaque deposition and age-related histological changes in associated brain pathology. The Aß present was of multiple forms, including species with a C-terminus at position 40 or 42, as well as an N-terminus at position 1 or truncated in a pyro-3-glutamate form. Endogenous rodent Aß was also present in the deposits. Laser capture microdissection extracts showed that multimeric forms of Aß were present in both plaque and tissue surrounding plaques. Associated with the Aß deposits was evidence of an inflammatory response characterised by the presence of astrocytes. Also present in close association with the deposits was phosphorylated tau and cathepsin D immunolabelling. The incidence of astrocytes and of phosphorylated tau and cathepsin D load showed that both of these potential disease markers increased in parallel to the age of the mice and with Aß deposition. Immunohistochemical labelling of neurons in the cortex and hippocampus of TASTPM mice suggested that the areas of Aß deposition were associated with the loss of neurons. TASTPM mice, therefore, exhibit a number of the pathological characteristics of disease progression in AD and may provide a means for assessment of novel therapeutic agents directed towards modifying or halting disease progression.