The inflammatory reaction at the vasculature may also be influenced by the adjuvant and carrier of choice, a process that may enhance clearance on the one hand but promote brain inflammation and microhaemorrhages on the other

The inflammatory reaction at the vasculature may also be influenced by the adjuvant and carrier of choice, a process that may enhance clearance on the one hand but promote brain inflammation and microhaemorrhages on the other. has taken several forms, from initially active to passive and then back to modified active vaccines. As the first two approaches to date failed to show sufficient efficacy, the last is presently being evaluated in ongoing clinical trials. The present review summarizes the immunogenic characteristics of A in humans and mice and discusses past, present and future A-based immunotherapeutic approaches for AD. We emphasize potential pathogenic and beneficial roles of CD4 T cells in light of the pathogenesis and the general decline in T-cell responsiveness evident in the disease. strong class=”kwd-title” Keywords: Alzheimer’s disease, amyloid -protein (A), CD4 T cells, A antibodies, immunotherapy Introduction Alzheimer’s disease (AD) is the most common form of dementia in the elderly, characterized by progressive memory loss and cognitive decline. One of the primary pathological features of the disease, in addition to neurofibrillary tangles, dystrophic neurites and significant neuronal loss in affected brain regions, is the extracellular aggregation of the amyloid -protein (A) peptide in the brain.1C4 Amyloid- is produced from the amyloid precursor protein (APP) following proteolytic cleavage by – and -secretases. Mutations in the preseneline-1 gene ( em PS1 /em ), which encodes for a transmembrane protein that functions as part of the -secretase complex, are associated with increased production of A42 over the less aggregative form A40, and are considered among the primary causes of early-onset familial AD.5,6 A growing body of evidence demonstrates that A plaques induce an inflammatory reaction in the brain,7C9 whereas oligomeric forms of A exert synaptotoxicity.3,4,10 In addition, in recent years information has accumulated demonstrating the marked pathological effects of A on brain vasculature, a phenomenon termed cerebral amyloid angiopathy, that causes vascular inflammation, brain haemorrhages, compromised perivascular drainage and altered blood flow.11C13 Inflammatory processes such as microgliosis, astrocytosis, dystrophic microglia, complement activation, cytokine elevation and acute-phase protein changes are thought to represent, at least in part, a response to the accumulation of A in the vasculature and parenchyma RSV604 R enantiomer of the brain. A compromised immune system associated with aging may substantially impact on these processes and lead to compromised brain function and neuronal repair processes, which enhance the progression of AD. The current review summarizes the existing knowledge regarding the characteristics of A-reactive CD4 T cells in animal models and in humans, and discusses A-based immunotherapeutic approaches for AD in the context of disease pathogenesis and immunosenescence. Main body A autoimmunity in humans and mice More than a decade ago a new concept emerged in the study of AD, namely eliciting adaptive immune responses to attenuate the accumulation of A RSV604 R enantiomer in the brain. This was the first time that a self peptide was introduced to the body as a vaccine, similar to classic vaccination approaches used against various pathogens. As this approach may have brought about the most promising therapeutic approach for AD, it also challenged our previous knowledge of autoimmunity, immune tolerance and brainCimmune interactions. Amyloid–specific immunotherapy can considerably reduce amyloid burden and improve cognitive functions in animal models of AD.14C21 Although pre-clinical studies have proved successful, an initial clinical trial of active A vaccine (AN-1792 trial performed by Elan) was halted because of the development of severe inflammatory reactions in the brains of some vaccinated AD patients.22C24 The severe side-effects were attributed to the use of the full length of the A peptide together with QS21, a very strong adjuvant, the combination of which presumably led to the occurrence of pathogenic T RSV604 R enantiomer cells Rabbit polyclonal to TLE4 at the brain vasculature and parenchyma.22,23,25 Nevertheless, the study of A-reactive T cells is key to unravelling their occurrence and characteristics in healthy humans as well as in patients with AD, and hence a key to designing safer immune-based approaches for AD therapy. Although the general dogma would not anticipate the occurrence of effector A-reactive CD4 T cells in the circulation of human subjects, not only were they detected in almost all individuals tested but significantly more elderly subjects and AD patients.