Chronic inflammation in response to Aß peptide deposits is a pathological hallmark of Alzheimer's disease (AD). The inflammatory environment includes populations of reactive and proliferating microglia and astrocytes and perturbed vasculature. However, the association between activated glial cells and cerebrovascular dysfunction remain largely unknown. This study has used Aß1-42 intrahippocampal injection as an animal model of inflamed AD brain to characterize mechanisms of glial-vasculature responses as a basis for chronic inflammation. Preliminary findings suggested Aß1-42-injected brain demonstrated vascular remodeling including evidence for formation of new blood vessels (angiogenesis). This result led to study of the effects of the anti-angiogenic/anti-inflammatory compound, thalidomide on activated glial cells and perturbations in the vasculature in an Aß1-42 peptide-injected rat model. First, Aß1-42 injection was found to cause perturbations in vasculature including new blood vessel formation and increased BBB leakiness. Second, thalidomide decreased the vascular perturbations and the glial reactivity and conferred neuroprotection. Overall, these results suggest that altered cerebral vasculature is integral to the overall inflammatory response induced by peptide. Experiments then examined the level of parenchymal plasma proteins in brain tissue from AD and nondemented (ND) individuals. AD, but not ND, brain tissue demonstrated high levels of fibrinogen immunoreactivity (ir). Aß1_42 injection into the rat hippocampus increased the level of parenchymal fibrinogen, which was reduced by treatment with the defibrinogenating agent, ancrod. In addition, ancrod also attenuated microglial activation and prevented neuronal injury. Overall, these results demonstrate that extravasation of blood protein and a leaky BBB are important in promoting and amplifying inflammatory responses and causing neuronal damage in inflamed AD brain. Microglial chemotactic responses to VEGF (vascular endothelial growth factor) receptor Flt-1 were next studied. Treatment with a monoclonal antibody to Flt-1 (anti-Flt-1 Ab) in the peptide-injected hippocampus diminished microglial reactivity and provided neuroprotection. Secondly, anti-Flt-1 Ab inhibited the AI3142-induced migration of human microglia. These results suggest critical functional roles for Flt-1 in mediating microglial chemotaxis and inflammatory responses in AD brain. The overall conclusion from my work is that AP deposits induce microglial reactivity which subsequently causes vascular remodeling resulting in an amplified inflammatory microenvironment which is damaging to bystander neurons.

Chronic inflammation in response to Aß peptide deposits is a pathological hallmark of Alzheimer's disease (AD). The inflammatory environment includes populations of reactive and proliferating microglia and astrocytes and perturbed vasculature. However, the association between activated glial cells and cerebrovascular dysfunction remain largely unknown. This study has used Aß1-42 intrahippocampal injection as an animal model of inflamed AD brain to characterize mechanisms of glial-vasculature responses as a basis for chronic inflammation. Preliminary findings suggested Aß1-42-injected brain demonstrated vascular remodeling including evidence for formation of new blood vessels (angiogenesis). This result led to study of the effects of the anti-angiogenic/anti-inflammatory compound, thalidomide on activated glial cells and perturbations in the vasculature in an Aß1-42 peptide-injected rat model. First, Aß1-42 injection was found to cause perturbations in vasculature including new blood vessel formation and increased BBB leakiness. Second, thalidomide decreased the vascular perturbations and the glial reactivity and conferred neuroprotection. Overall, these results suggest that altered cerebral vasculature is integral to the overall inflammatory response induced by peptide. Experiments then examined the level of parenchymal plasma proteins in brain tissue from AD and nondemented (ND) individuals. AD, but not ND, brain tissue demonstrated high levels of fibrinogen immunoreactivity (ir). Aß1_42 injection into the rat hippocampus increased the level of parenchymal fibrinogen, which was reduced by treatment with the defibrinogenating agent, ancrod. In addition, ancrod also attenuated microglial activation and prevented neuronal injury. Overall, these results demonstrate that extravasation of blood protein and a leaky BBB are important in promoting and amplifying inflammatory responses and causing neuronal damage in inflamed AD brain. Microglial chemotactic responses to VEGF (vascular endothelial growth factor) receptor Flt-1 were next studied. Treatment with a monoclonal antibody to Flt-1 (anti-Flt-1 Ab) in the peptide-injected hippocampus diminished microglial reactivity and provided neuroprotection. Secondly, anti-Flt-1 Ab inhibited the AI3142-induced migration of human microglia. These results suggest critical functional roles for Flt-1 in mediating microglial chemotaxis and inflammatory responses in AD brain. The overall conclusion from my work is that AP deposits induce microglial reactivity which subsequently causes vascular remodeling resulting in an amplified inflammatory microenvironment which is damaging to bystander neurons.

Chronic inflammation in response to Aß peptide deposits is a pathological hallmark of Alzheimer's disease (AD). The inflammatory environment includes populations of reactive and proliferating microglia and astrocytes and perturbed vasculature. However, the association between activated glial cells and cerebrovascular dysfunction remain largely unknown. This study has used Aß1-42 intrahippocampal injection as an animal model of inflamed AD brain to characterize mechanisms of glial-vasculature responses as a basis for chronic inflammation. Preliminary findings suggested Aß1-42-injected brain demonstrated vascular remodeling including evidence for formation of new blood vessels (angiogenesis). This result led to study of the effects of the anti-angiogenic/anti-inflammatory compound, thalidomide on activated glial cells and perturbations in the vasculature in an Aß1-42 peptide-injected rat model. First, Aß1-42 injection was found to cause perturbations in vasculature including new blood vessel formation and increased BBB leakiness. Second, thalidomide decreased the vascular perturbations and the glial reactivity and conferred neuroprotection. Overall, these results suggest that altered cerebral vasculature is integral to the overall inflammatory response induced by peptide. Experiments then examined the level of parenchymal plasma proteins in brain tissue from AD and nondemented (ND) individuals. AD, but not ND, brain tissue demonstrated high levels of fibrinogen immunoreactivity (ir). Aß1_42 injection into the rat hippocampus increased the level of parenchymal fibrinogen, which was reduced by treatment with the defibrinogenating agent, ancrod. In addition, ancrod also attenuated microglial activation and prevented neuronal injury. Overall, these results demonstrate that extravasation of blood protein and a leaky BBB are important in promoting and amplifying inflammatory responses and causing neuronal damage in inflamed AD brain. Microglial chemotactic responses to VEGF (vascular endothelial growth factor) receptor Flt-1 were next studied. Treatment with a monoclonal antibody to Flt-1 (anti-Flt-1 Ab) in the peptide-injected hippocampus diminished microglial reactivity and provided neuroprotection. Secondly, anti-Flt-1 Ab inhibited the AI3142-induced migration of human microglia. These results suggest critical functional roles for Flt-1 in mediating microglial chemotaxis and inflammatory responses in AD brain. The overall conclusion from my work is that AP deposits induce microglial reactivity which subsequently causes vascular remodeling resulting in an amplified inflammatory microenvironment which is damaging to bystander neurons. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Alzheimer-Demenz ist eine Erkrankung, die durch den demografischen Wandel immer mehr an Bedeutung gewinnt. Eine effektive und frühzeitige Diagnostik ist daher entschei-dend. Da die neuropsychiatrische Testung mit einer diagnostischen Unsicherheit von 10% bis 30% zu ungenau ist und auch erst bei Ausbruch der Symptomatik eine Alzheimer-Demenz diagnostiziert werden kann, wurde auf Parameter wie Beta-Amyloid zurückgegrif-fen. Beta-Amyloid stellt einen Hauptbestandteil der Alzheimer-Demenz Pathologie dar und ist bereits vor Ausbruch der Symptome nachweisbar. Da die visuelle Analyse, welche die Beta-Amyloid Hirn-PET-Daten auswertet, durch ihren hohen Zeitaufwand im Alltag nicht einsetzbar ist, wurden automatische Auswerteverfahren entwickelt. Das BRASS zeigt sich mit einer Sensitivität von 78,4% und einer Spezifität von 80,5% im Bezug zur visuellen Analyse als gut geeignet in der Differenzierung zwischen Probanden mit und ohne Anreicherung von Beta-Amyloid. Eine weitere Verbesserung der Ergebnisse ist durch eine ROC-Analyse im Bezug zu den histopathologischen Befunden vorstellbar, welches in Phase 3 der Studie überprüft wird. Innerhalb des BRASS sind bei der Testung einige Schwierigkeiten aufgetreten, die bei der Weiterentwicklung der Software berücksichtigt und verbessert werden müssen. Auch dadurch ist mit einer weiteren Erhöhung der Sensitivität und Spezifität zu rechnen, sodass der Einsatz des BRASS als ein Standardver-fahren in der Alzheimer-Demenz Diagnostik realistisch ist.

No description available.

No description available.

Alzheimer-Demenz ist eine Erkrankung, die durch den demografischen Wandel immer mehr an Bedeutung gewinnt. Eine effektive und frühzeitige Diagnostik ist daher entschei-dend. Da die neuropsychiatrische Testung mit einer diagnostischen Unsicherheit von 10% bis 30% zu ungenau ist und auch erst bei Ausbruch der Symptomatik eine Alzheimer-Demenz diagnostiziert werden kann, wurde auf Parameter wie Beta-Amyloid zurückgegrif-fen. Beta-Amyloid stellt einen Hauptbestandteil der Alzheimer-Demenz Pathologie dar und ist bereits vor Ausbruch der Symptome nachweisbar. Da die visuelle Analyse, welche die Beta-Amyloid Hirn-PET-Daten auswertet, durch ihren hohen Zeitaufwand im Alltag nicht einsetzbar ist, wurden automatische Auswerteverfahren entwickelt. Das BRASS zeigt sich mit einer Sensitivität von 78,4% und einer Spezifität von 80,5% im Bezug zur visuellen Analyse als gut geeignet in der Differenzierung zwischen Probanden mit und ohne Anreicherung von Beta-Amyloid. Eine weitere Verbesserung der Ergebnisse ist durch eine ROC-Analyse im Bezug zu den histopathologischen Befunden vorstellbar, welches in Phase 3 der Studie überprüft wird. Innerhalb des BRASS sind bei der Testung einige Schwierigkeiten aufgetreten, die bei der Weiterentwicklung der Software berücksichtigt und verbessert werden müssen. Auch dadurch ist mit einer weiteren Erhöhung der Sensitivität und Spezifität zu rechnen, sodass der Einsatz des BRASS als ein Standardver-fahren in der Alzheimer-Demenz Diagnostik realistisch ist.

This dissertation is a critical examination of the relationship between sleep problems and/or disorders, particularly Obstructive Sleep Apnea (OSA) and Alzheimer Disease (AD). First, I conducted an exhaustive systematic review of existing literature, and identified gaps in research that led to specific research aims. For the first aim, I conducted the first ever-published meta-analysis examining sleep, cognitive decline and AD, providing an aggregate effect of sleep on AD. Second, focusing on OSA, I conducted a study examining OSA’s effect on longitudinal changes on AD biomarkers in cognitive normal, MCI and AD subjects, using data from the Alzheimer Disease Neuroimaging Initiative (ADNI). Lastly, I conducted a review, integrating over 3 decades of research examining OSA and cognition; OSA and subsequent cognitive decline; and OSA and AD; with particular focus in appreciating the heterogeneity of OSA and its outcomes in distinct age groups. Results and implications from my research indicate that ample evidence exists linking sleep impairments and circadian regulating mechanisms directly to clinical symptoms in AD. Sleep problems and/or disorders increases your risk of cognitive decline and AD. OSA is associated with increased AD biomarker burden over time, and effects longitudinal changes in these biomarkers, such that OSA subjects progress faster than non-OSA subjects do. OSA may be age-dependent in older adults (60 – 70 years old) and the elderly (70 years and above) and is associated with neurodegenerative diseases particularly, cognitive decline and AD. Intermittent hypoxia and sleep fragmentation are two main processes by which OSA induces neurodegenerative changes. Therefore, clinical interventions aimed at OSA, such as treatment with CPAP or dental appliances, in cognitive normal and MCI patients, could possibly slow the progression of cognitive impairment to AD.

b-amyloid is derived from amyloid precursor protein (APP) and tightly associated with the pathogenesis of Alzheimer¡¦s disease (AD). Structurally, APP belongs to type I transmembrane protein family and is composed of a large glycosylated extracellular component, a single membrane-spanning region, and a short cytoplasmic domain. Although physiological function of APP remains unclear, the proteolytic processing of APP by b secretase and g secretase gives rise to the production and secretion of b-amyloid. The C-terminus of APP is believed to participate in the intracellular trafficking of APP and signal transduction via interacting with adaptors and signaling proteins, respectively. Three phosphorylation sites (Thr654, Ser655 and Thr668, numbering for APP695 isoform) and several functional motifs in the cytoplasmic domain of APP have been identified and demonstrated that the phosphorylation can indeed affect APP metabolism including: the rate of secretion, endocytosis and b-amyloid production. In this study, we focused on how APP binding protein1 and the phosphorylation affect on APP metabolism. The reasons are as following: (1) Among many APP associated proteins, APP binding protein 1 (APPBP1) is involved in S-M checkpoint regulation. (2) Recent evidence indicates that aberrantly activation of mitotic events may play an important role in development of AD. Since progression through mitosis is regulated by Cdc2 that has been demonstrated to phosphorylate APP on Thr668-Pro669, the phosphorylation of APP at Thr668 may play the important role in regulating APP metabolism and may also relate to AD development. (3) Moreover, protein phosphorylation induces the conformational change and affects the protein- protein interaction. Phosphorylation of Ser / Thr-Pro motif is a central mechanism controlling progression of the cell cycle, including mitosis. Proline residues provide a potential backbone switch in the polypeptide chain controlled by the cis / trans isomerization. Pin1 is an important mitotic regulator and a highly specific peptidyl-prolyl cis / trans isomerases (PPIase) that catalyzes the isomerization of phosphorylated Ser / Thr-Pro bonds. Our unpublished data have shown that Pin1 can bind to the phosphorylated Thr668-Pro669 APP peptide with high affinity (20 nM) that suggested that Pin1 may interact and regulate mitotic APP. Taken together, these data suggested that the interaction of APP and APPBP1 or Pin1 may affect the APP metabolism and its physiological function. This study investigated the hypothesis above and revealed includes the following results (i) the subcellular localization of the C-terminus of APP and APPBP1; (ii) the interaction between APPBP1 and the C-terminus of APP in vivo and in vitro; (iii) Thr668 of APP is the Cdc2 phosphorylation site; (iv) the binding of APPBP1 to the C-terminus of APP reduces the phosphorylation of APP by Cdc2; (v) the phosphorylation at Thr668 can abolish the interaction between APPBP1 and the C-terminus of APP; (vi) the C-terminus of APP is one of the caspase 3 targets; (vii) the phosphorylation of APP at Thr668 also reduces the caspase 3 activity forward to the C-terminus of APP cleavage; (viii) both APPBP1 and Pin1 can inhibit the C-terminus of APP cleavage by caspase 3 that suggested two novel mechanisms to regulate APP metabolism.

No description available.