Ulrike Obermüller

Peripherally Applied Aβ-Containing Inoculates Induce Cerebral β-Amyloidosis

Infectious Amyloid? Patients with Alzheimers disease have characteristic lesions in the brains associated with masses of polymerized protein called β-amyloid. Recently, evidence from mouse models of Alzheimers disease shows that brain extracts containing β-amyloid can “infect” otherwise healthy animals when injected directly into their brains. Eisele et al. (p. 980, published online 21 October; see the Perspective by Kim and Holtzman) extend these findings to show that when mice are injected in other parts of their bodies with similar brain extracts after several months, they also develop amyloidosis within their brains. Amyloid-containing brain extracts can “infect” susceptible Alzheimer’s disease model animals. The intracerebral injection of β-amyloid–containing brain extracts can induce cerebral β-amyloidosis and associated pathologies in susceptible hosts. We found that intraperitoneal inoculation with β-amyloid–rich extracts induced β-amyloidosis in the brains of β-amyloid precursor protein transgenic mice after prolonged incubation times.

Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis.

Infectious Amyloid? Patients with Alzheimers disease have characteristic lesions in the brains associated with masses of polymerized protein called β-amyloid. Recently, evidence from mouse models of Alzheimers disease shows that brain extracts containing β-amyloid can “infect” otherwise healthy animals when injected directly into their brains. Eisele et al. (p. 980, published online 21 October; see the Perspective by Kim and Holtzman) extend these findings to show that when mice are injected in other parts of their bodies with similar brain extracts after several months, they also develop amyloidosis within their brains. Amyloid-containing brain extracts can “infect” susceptible Alzheimer’s disease model animals. The intracerebral injection of β-amyloid–containing brain extracts can induce cerebral β-amyloidosis and associated pathologies in susceptible hosts. We found that intraperitoneal inoculation with β-amyloid–rich extracts induced β-amyloidosis in the brains of β-amyloid precursor protein transgenic mice after prolonged incubation times.

Synergistic antiglioma activity of radiotherapy and enzastaurin

Radiotherapy is an essential treatment modality for malignant gliomas, but it exerts adverse effects via promotion of glioma cell invasion in experimental glioma. Furthermore, irradiation induces vascular endothelial growth factor (VEGF) levels in gliomas, which is associated with poor prognosis. Here, we investigate the combination of the protein kinase C‐β inhibitor enzastaurin (ENZA) and radiotherapy in vitro and in vivo in comparison with either treatment alone.

Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging

To clarify the role of microglia in brain homeostasis and disease, an understanding of their maintenance, proliferation and turnover is essential. The lifespan of brain microglia, however, remains uncertain, and reflects confounding factors in earlier assessments that were largely indirect. We genetically labeled single resident microglia in living mice and then used multiphoton microscopy to monitor these cells over time. Under homeostatic conditions, we found that neocortical resident microglia were long-lived, with a median lifetime of well over 15 months; thus, approximately half of these cells survive the entire mouse lifespan. While proliferation of resident neocortical microglia under homeostatic conditions was low, microglial proliferation in a mouse model of Alzheimers β-amyloidosis was increased threefold. The persistence of individual microglia throughout the mouse lifespan provides an explanation for how microglial priming early in life can induce lasting functional changes and how microglial senescence may contribute to age-related neurodegenerative diseases.

Multiple factors contribute to the peripheral induction of cerebral beta-amyloidosis

Deposition of aggregated amyloid-β (Aβ) peptide in brain is an early event and hallmark pathology of Alzheimers disease and cerebral Aβ angiopathy. Experimental evidence supports the concept that Aβ multimers can act as seeds and structurally corrupt other Aβ peptides by a self-propagating mechanism. Here we compare the induction of cerebral β-amyloidosis by intraperitoneal applications of Aβ-containing brain extracts in three Aβ-precursor protein (APP) transgenic mouse lines that differ in levels of transgene expression in brain and periphery (APP23 mice, APP23 mice lacking murine APP, and R1.40 mice). Results revealed that beta-amyloidosis induction, which could be blocked with an anti-Aβ antibody, was dependent on the amount of inoculated brain extract and on the level of APP/Aβ expression in the brain but not in the periphery. The induced Aβ deposits in brain occurred in a characteristic pattern consistent with the entry of Aβ seeds at multiple brain locations. Intraperitoneally injected Aβ could be detected in blood monocytes and some peripheral tissues (liver, spleen) up to 30 d after the injection but escaped histological and biochemical detection thereafter. These results suggest that intraperitoneally inoculated Aβ seeds are transported from the periphery to the brain in which corruptive templating of host Aβ occurs at multiple sites, most efficiently in regions with high availability of soluble Aβ.

Peripherally Applied A -Containing Inoculates Induce Cerebral -Amyloidosis

Infectious Amyloid? Patients with Alzheimers disease have characteristic lesions in the brains associated with masses of polymerized protein called β-amyloid. Recently, evidence from mouse models of Alzheimers disease shows that brain extracts containing β-amyloid can “infect” otherwise healthy animals when injected directly into their brains. Eisele et al. (p. 980, published online 21 October; see the Perspective by Kim and Holtzman) extend these findings to show that when mice are injected in other parts of their bodies with similar brain extracts after several months, they also develop amyloidosis within their brains. Amyloid-containing brain extracts can “infect” susceptible Alzheimer’s disease model animals. The intracerebral injection of β-amyloid–containing brain extracts can induce cerebral β-amyloidosis and associated pathologies in susceptible hosts. We found that intraperitoneal inoculation with β-amyloid–rich extracts induced β-amyloidosis in the brains of β-amyloid precursor protein transgenic mice after prolonged incubation times.

Persistence of Aβ seeds in APP null mouse brain.

Cerebral β-amyloidosis is induced by inoculation of Aβ seeds into APP transgenic mice, but not into App−/− (APP null) mice. We found that brain extracts from APP null mice that had been inoculated with Aβ seeds up to 6 months previously still induced β-amyloidosis in APP transgenic hosts following secondary transmission. Thus, Aβ seeds can persist in the brain for months, and they regain propagative and pathogenic activity in the presence of host Aβ.

Increased CSF Aβ during the very early phase of cerebral Aβ deposition in mouse models

Abnormalities in brains of Alzheimers disease (AD) patients are thought to start long before the first clinical symptoms emerge. The identification of affected individuals at this ‘preclinical AD’ stage relies on biomarkers such as decreased levels of the amyloid‐β peptide (Aβ) in the cerebrospinal fluid (CSF) and positive amyloid positron emission tomography scans. However, there is little information on the longitudinal dynamics of CSF biomarkers, especially in the earliest disease stages when therapeutic interventions are likely most effective. To this end, we have studied CSF Aβ changes in three Aβ precursor protein transgenic mouse models, focusing our analysis on the initial Aβ deposition, which differs significantly among the models studied. Remarkably, while we confirmed the CSF Aβ decrease during the extended course of brain Aβ deposition, a 20–30% increase in CSF Aβ40 and Aβ42 was found around the time of the first Aβ plaque appearance in all models. The biphasic nature of this observed biomarker changes stresses the need for longitudinal biomarker studies in the clinical setting and the search for new ‘preclinical AD’ biomarkers at even earlier disease stages, by using both mice and human samples. Ultimately, our findings may open new perspectives in identifying subjects at risk for AD significantly earlier, and in improving the stratification of patients for preventive treatment strategies.

Progression of Seed-Induced Aβ Deposition within the Limbic Connectome

An important early event in the pathogenesis of Alzheimers disease (AD) is the aberrant polymerization and extracellular accumulation of amyloid‐β peptide (Aβ). In young transgenic mice expressing the human Aβ‐precursor protein (APP), deposits of Aβ can be induced by the inoculation of minute amounts of brain extract containing Aβ aggregates (“Aβ seeds”), indicative of a prion‐like seeding phenomenon. Moreover, focal intracerebral injection of Aβ seeds can induce deposits not only in the immediate vicinity of the injection site, but, with time, also in distal regions of the brain. However, it remains uncertain whether the spatial progression of Aβ deposits occurs via nonsystematic diffusion from the injection site to proximal regions or via directed transit along neuroanatomical pathways. To address this question, we analyzed the spatiotemporal emergence of Aβ deposits in two different APP‐transgenic mouse models that had been previously inoculated with Aβ seeds into the hippocampal formation. The results revealed a specific, neuroanatomically constrained pattern of induced Aβ deposits in structures corresponding to the limbic connectome, supporting the hypothesis that neuronal pathways act as conduits for the movement of proteopathic agents among brain regions, thereby facilitating the progression of disease.

Aβ seeding potency peaks in the early stages of cerebral β‐amyloidosis

Little is known about the extent to which pathogenic factors drive the development of Alzheimers disease (AD) at different stages of the long preclinical and clinical phases. Given that the aggregation of the β‐amyloid peptide (Aβ) is an important factor in AD pathogenesis, we asked whether Aβ seeds from brain extracts of mice at different stages of amyloid deposition differ in their biological activity. Specifically, we assessed the effect of age on Aβ seeding activity in two mouse models of cerebral Aβ amyloidosis (APPPS1 and APP23) with different ages of onset and rates of progression of Aβ deposition. Brain extracts from these mice were serially diluted and inoculated into host mice. Strikingly, the seeding activity (seeding dose SD50) in extracts from donor mice of both models reached a plateau relatively early in the amyloidogenic process. When normalized to total brain Aβ, the resulting specific seeding activity sharply peaked at the initial phase of Aβ deposition, which in turn is characterized by a temporary several‐fold increase in the Aβ42/Aβ40 ratio. At all stages, the specific seeding activity of the APPPS1 extract was higher compared to that of APP23 brain extract, consistent with a more important contribution of Aβ42 than Aβ40 to seed activity. Our findings indicate that the Aβ seeding potency is greatest early in the pathogenic cascade and diminishes as Aβ increasingly accumulates in brain. The present results provide experimental support for directing anti‐Aβ therapeutics to the earliest stage of the pathogenic cascade, preferably before the onset of amyloid deposition.