Amyloid-Associated Neuron Loss and Gliogenesis in the Neocortex of Amyloid Precursor Protein Transgenic Mice

Abstract

APP23 transgenic mice express mutant human amyloid precursor protein and develop amyloid plaques predominantly in neocortex and hippocampus progressively with age, similar to Alzheimer's disease. We have previously reported neuron loss in the hippocampal CA1 region of 14-to 18-month-old APP23 mice. In contrast, no neuron loss was found in neocortex. In the present study we have reinvestigated neocortical neuron numbers in adult and aged APP23 mice. Surprisingly, results revealed that 8-month-old APP23 mice have 13 and 14% more neocortical neurons compared with 8-month-old wild-type and 27-month-old APP23 mice, respectively. In 27-month-old APP23 mice we found an inverse correlation between amyloid load and neuron number. These results suggest that APP23 mice have more neurons until they develop amyloid plaques but then lose neurons in the process of cerebral amyloidogenesis. Supporting this notion, we found more neurons with a necroticapoptotic phenotype in the neocortex of 24-month-old APP23 mice compared with age-matched wild-type mice. Stimulated by recent reports that demonstrated neurogenesis after targeted neuron death in the mouse neocortex, we have also examined neurogenesis in APP23 mice. Strikingly, we found a fourfold to sixfold increase in newly produced cells in 24-month-old APP23 mice compared with both age-matched wildtype mice and young APP23 transgenic mice. However, subsequent cellular phenotyping revealed that none of the newly generated cells in neocortex had a neuronal phenotype. The majority were microglial and to a lesser extent astroglial cells. We conclude that cerebral amyloidosis in APP23 mice causes a modest neuron loss in neocortex and induces marked gliogenesis.

Amyloid precursor protein increases cortical neuron size in transgenic mice

“…Besides the absence of neurofibrillary changes, most of these animal models do not demonstrate overt neuronal loss (Irizarry et al, 1997a, b ), with some exceptions (Calhoun et al, 1998). Several explanations have been proposed for this phenomenon including species variability in neuronal vulnerability, lack of certain human-type inflammatory factors and tau protein (Hardy and Selkoe, 2002), as well as species variability in Aβ burden and different types of plaques that accumulate in different tg mouse models (Bondolfi et al, 2002). Given our data, it is possible that the neurotrophic effects of APP overexpression may protect the brain of these animals from Aβ-mediated neuronal injury and loss.…”

Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine

“…APP expression is also increased after brain injury, and increased levels are observed in apoptotic cells (11,12). Other studies report that A␤ inhibits NSC migration by increasing amyloid-associated cell death and by dysregulation of cellular calcium homeostasis (13,14). These findings suggest that not only A␤ but that also altered APP processing during the course of AD may have effects on stem cell biology.…”

Expression pattern of the transcription factor Olig2 in response to brain injuries: Implications for neuronal repair

“…To understand to which extent the results described above have general implications for adult brain injury, we examined other lesion models, comprising a further acute injury, the MCAO as a model for stroke (25), and a chronic injury paradigm with amyloid plaque deposition in transgenic mice expressing the mutated forms of APP (27) and PS1 (28) under the Thy-1 promoter (Thy1-APPPS, see Materials and Methods). Despite the huge difference between these injury models, the number of Olig2ϩ cells increased in all of these injury paradigms (Fig.…”