A Changing Perspective on the Role of Neuroinflammation in Alzheimer\u27s Disease

Alzheimer\u27s disease (AD) is a complex, neurodegenerative disorder characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain. Glial cells, particularly microglial cells, react to the presence of the amyloid plaques and neurofibrillary tangles producing an inflammatory response. While once considered immunologically privileged due to the blood-brain barrier, it is now understood that the glial cells of the brain are capable of complex inflammatory responses. This paper will discuss the published literature regarding the diverse roles of neuroinflammation in the modulation of AD pathologies. These data will then be related to the well-characterized macrophage phenotypes. The conclusion is that the glial cells of the brain are capable of a host of macrophage responses, termed M1, M2a, M2b, and M2c. The relationship between these states and AD pathologies remains relatively understudied, yet published data using various inflammatory stimuli provides some insight. It appears that an M1-type response lowers amyloid load but exacerbates neurofibrillary tangle pathology. In contrast, M2a is accompanied by elevated amyloid load and appears to ameliorate, somewhat, neurofibrillary pathology. Overall, it is clear that more focused, cause-effect studies need to be performed to better establish how each inflammatory state can modulate the pathologies of AD

Investigation of the Sn-P bond and related studies

This thesis reports the synthesis and analysis of a number of organometallic compounds, focusing primarily on novel structures containing Sn and P atoms. Chapter 1 contains a literature review examining the different structural and bonding properties and reactions of C4H4, P4 and P2C2R2. Chapter2 describes the ability of the P2C2tBu2 ligand to cause a reductive elimination in Sn(IV) species. Several different products from the reaction between Me2SnCl2 and Cp2Zr(P2C2tBu2) are determined, and mechanisms for their interconversion are proposed. The synthesis of Sn(P2C2Ad2) is reported along with its unprecedentedly low frequency 119Sn NMR spectroscopic chemical shift. Chapter 3 contains attempts to produce transition metal complexes with phosphaalkyne based ligands. The crystal structure of a complex containing Fe and Zr centres with two P2C2Ad2 rings is reported along with analysis of its paramagnetism. Mechanisms for the exchange of P2C2R2 rings and chlorides are also proposed. Chapter 4 details the synthesis of a range of CpnSnIm species and a comparison of their solid and solution state structures using X-ray diffraction and NMR spectroscopy. Reactions between these compounds and P(SiMe3)3 or LiP(SiMe3)2 are performed in order to explore the possibility of forming a Sn-P multiple bond. Chapter 5 outlines the synthesis of bicyclic systems based on C6H4-1,2-(PH2)2 and Sn and Ge dialkyls. The effect of alkyl group bulk on product structure is investigated. Chapter 6 explores the reaction between C6H4-1,2-(PH2)2 and P(SiMe3)3 in which an exchange of H and SiMe3 groups occurs. The mechanism of the reaction is elucidated by the introduction of a catalytic proton source

The Flushing Flow Problem: Defining and Evaluating Objectives

Reservoir releases may be specified for the purpose of maintaining or improving the downstream channel and habitat. A wide variety of ecological or management objectives may be defined for such flushing flows (which may be broadly divided into sediment maintenance and channel maintenance flows). To specify a particular discharge and water volume for a flushing flow requires that the ecological or management objectives be translated into specific physical objectives for which flows can be specified. Flushing objectives that cannot be translated into definable flows are of little practical use, regardless of their intrinsic importance. Once defined, flushing flow objectives may be shown to conflict in some cases. For example, no flushing flow can satisfy the typical sediment maintenance objectives of maximizing sand removal and minimizing gravel loss. A discharge that mobilizes sediment throughout the channel cross section for channel maintenance purposes will often produce comparable transport rates of sand and gravel, thereby eliminating the selective transport of sand needed to reduce the sand content in the bed. Some nonflushing alternatives, such as artificial gravel replenishment and pool dredging, can be used to improve the performance of flushing flows. Selection among these alternatives and specification of a flushing flow discharge and volume depend directly on quantitative estimates of sand and gravel transport as a function of flow rate and volume

Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage

BACKGROUND: Anti-Aβ immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Aβ antibodies to 19- and 23-month old APP-transgenic mice. METHODS: We investigated the effects of weekly anti-Aβ antibody treatment on radial-arm water-maze performance, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing. RESULTS: After 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Aβ immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy. CONCLUSIONS: The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage

Dysregulation of Na+/K+ ATPase by amyloid in APP+PS1 transgenic mice

BACKGROUND: The pathology of Alzheimer's disease (AD) is comprised of extracellular amyloid plaques, intracellular tau tangles, dystrophic neurites and neurodegeneration. The mechanisms by which these various pathological features arise are under intense investigation. Here, expanding upon pilot gene expression studies, we have further analyzed the relationship between Na+/K+ ATPase and amyloid using APP+PS1 transgenic mice, a model that develops amyloid plaques and memory deficits in the absence of tangle formation and neuronal or synaptic loss. RESULTS: We report that in addition to decreased mRNA expression, there was decreased overall Na+/K+ ATPase enzyme activity in the amyloid-containing hippocampi of the APP+PS1 mice (although not in the amyloid-free cerebellum). In addition, dual immunolabeling revealed an absence of Na+/K+ ATPase staining in a zone surrounding congophilic plaques that was occupied by dystrophic neurites. We also demonstrate that cerebral Na+/K+ ATPase activity can be directly inhibited by high concentrations of soluble Aβ. CONCLUSIONS: The data suggest that the reductions in Na+/K+ ATPase activity in Alzheimer tissue may not be purely secondary to neuronal loss, but may results from direct effects of amyloid on this enzyme. This disruption of ion homeostasis and osmotic balance may interfere with normal electrotonic properties of dendrites, blocking intraneuronal signal processing, and contribute to neuritic dystrophia. These results suggest that therapies aimed at enhancing Na+/K+ ATPase activity in AD may improve symptoms and/or delay disease progression

Down\u27s syndrome, neroinflammation, and Alzheimer neuropathogenesis

Down syndrome (DS) is the result of triplication of chromosome 21 (trisomy 21) and is the prevailing cause of mental retardation. In addition to the mental deficiencies and physical anomalies noted at birth, triplication of chromosome 21 gene products results in the neuropathological and cognitive changes of Alzheimer\u27s disease (AD). Mapping of the gene that encodes the precursor protein (APP) of the β-amyloid (Aβ) present in the Aβ plaques in both AD and DS to chromosome 21 was strong evidence that this chromosome 21 gene product was a principal neuropathogenic culprit in AD as well as DS. The discovery of neuroinflammatory changes, including dramatic proliferation of activated glia overexpressing a chromosome 2 gene product--the pluripotent immune cytokine interleukin-1 (IL-1)--and a chromosome 21 gene product--S100B--in the brains of fetuses, neonates, and children with DS opened the possibility that early events in Alzheimer pathogenesis were driven by cytokines. The specific chromosome 21 gene products and the complexity of the mechanisms they engender that give rise to the neuroinflammatory responses noted in fetal development of the DS brain and their potential as accelerators of Alzheimer neuropathogenesis in DS are topics of this review, particularly as they relate to development and propagation of neuroinflammation, the consequences of which are recognized clinically and neuropathologically as Alzheimer\u27s disease

Hyperhomocysteinemia as a Risk Factor for Vascular Contributions to Cognitive Impairment and Dementia

Behind only Alzheimer’s disease, vascular contributions to cognitive impairment and dementia (VCID) is the second most common cause of dementia, affecting roughly 10–40% of dementia patients. While there is no cure for VCID, several risk factors for VCID, such as diabetes, hypertension, and stroke, have been identified. Elevated plasma levels of homocysteine, termed hyperhomocysteinemia (HHcy), are a major, yet underrecognized, risk factor for VCID. B vitamin deficiency, which is the most common cause of HHcy, is common in the elderly. With B vitamin supplementation being a relatively safe and inexpensive therapeutic, the treatment of HHcy-induced VCID would seem straightforward; however, preclinical and clinical data shows it is not. Clinical trials using B vitamin supplementation have shown conflicting results about the benefits of lowering homocysteine and issues have arisen over proper study design within the trials. Studies using cell culture and animal models have proposed several mechanisms for homocysteine-induced cognitive decline, providing other targets for therapeutics. For this review, we will focus on HHcy as a risk factor for VCID, specifically, the different mechanisms proposed for homocysteine-induced cognitive decline and the clinical trials aimed at lowering plasma homocysteine