Biomedical subjects

Mathias Jucker

Publications and source records attributed to Mathias Jucker.

23 records · Page 2Linked to original sources

PubMed2003

Extracellular amyloid formation and associated pathology in neural grafts.

Amyloid precursor protein (APP) processing and the generation of beta-amyloid peptide (Abeta) are important in the pathogenesis of Alzheimer's disease. Although this has been studied extensively at the molecular and cellular levels, much less is known about the mechanisms of amyloid accumulation in vivo. We transplanted transgenic APP23 and wild-type B6 embryonic neural cells into the neocortex and hippocampus of both B6 and APP23 mice. APP23 grafts into wild-type hosts did not develop amyloid deposits up to 20 months after grafting. In contrast, both transgenic and wild-type grafts into young transgenic hosts developed amyloid plaques as early as 3 months after grafting. Although largely diffuse in nature, some of the amyloid deposits in wild-type grafts were congophilic and were surrounded by neuritic changes and gliosis, similar to the amyloid-associated pathology previously described in APP23 mice. Our results indicate that diffusion of soluble Abeta in the extracellular space is involved in the spread of Abeta pathology, and that extracellular amyloid formation can lead to neurodegeneration.

Alzheimer Disease↗

PubMed2002

Age and gender effects on microglia and astrocyte numbers in brains of mice.

The morphological changes that occur during normal brain aging are not well understood. This study used modern stereology to assess the effects of age and gender on total numbers of astrocytes and microglia in the hippocampal formation in C57Bl/6NNIA (B6) mice. Astrocytes and microglia were visualized using immunocytochemistry for glial fibrillary acidic protein (GFAP) and complement receptor 3 (Mac-1), respectively, and numbers of each cell type in dentate gyrus (DG) and CA1 regions were estimated using the optical fractionator method. The results reveal significantly greater ( approximately 20%) numbers of microglia and astrocytes in aged females compared to young female B6 mice. We also report that on average female B6 mice have 25-40% more astrocytes and microglia in DG and CA1 regions than age-matched male C57Bl/6J mice. Since astrocytes and microglia are thought to be targets of gonadal hormones, the effects of sex hormones and reproductive aging may be responsible for these findings.

Age Factors↗

PubMed2002

Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis.

Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral beta-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.

Acetylcholinesterase↗

PubMed2002

Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice.

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 necrotic-apoptotic 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 wild-type 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.

Aging↗

PubMed2002

Thrombolysis induces cerebral hemorrhage in a mouse model of cerebral amyloid angiopathy.

We studied the impact of cerebral amyloid angiopathy on tissue plasminogen activator-induced cerebral hemorrhages in APP23 transgenic mice. Results show that the intravenous administration of tissue plasminogen activator in APP23 mice leads to an increase in cerebral amyloid angiopathy-associated microhemorrhages and can provoke parenchymal and subarachnoidal hematomas. We conclude that cerebral amyloid angiopathy is a risk factor for cerebral hemorrhage caused by tissue plasminogen activator administration in mice and stress the need for more comprehensive studies of the relation between cerebral amyloid angiopathy and tissue plasminogen activator-induced cerebral hemorrhages in elderly and Alzheimer's disease patients.

Animals↗