1996;274:99C102. active immunization advanced to clinical trials a subset of patients developed meningoencephalitis; an event not predicted in mouse studies. However, it was suspected that a T-cell response due to the type of adjuvant used was the cause of the meningoencephalitis and studies in mice indicated alternative methods of vaccination. Passive immunization has also advanced to phase III clinical trials on the basis of successful transgenic mouse studies. Reports from the active immunization clinical trial indicated that, indeed, amyloid levels in brain were reduced. While APP transgenic mouse models are useful in studying amyloid pathology these mice do not generate significant tau pathology or neuron loss. Continued development of new mouse models that do generate all of Azilsartan (TAK-536) these pathologies will be critical in more accurately testing therapeutics and predicting the clinical outcome of such therapeutics. Alzheimer’s disease and the amyloid hypothesis Alzheimer’s disease (AD) is a neurodegenerative disorder leading to a dementia with progressive loss of brain function. The primary risk Azilsartan (TAK-536) factor for AD is age, with onset typically in the 70s?90s. The mean life expectancy is anywhere from 7 to 15 years after the initial diagnosis, however, rates of progression vary significantly between patients. While diagnosis of AD may be made through a battery of cognitive tests, a definite diagnosis can only be made at autopsy by microscopic examination of the brain tissue. According to the NIA-Reagan criteria a diagnosis of AD requires the presence of amyloid deposits, neurofibrillary tangles and neurodegeneration as well as dementia [1]. Amyloid plaques are insoluble, extracellular accumulations of amyloid-beta Azilsartan (TAK-536) (A) peptides. Neurofibrillary tangles are intraneuronal accumulations of hyperphosphorylated, aggregated tau protein (a microtubule binding protein) that redistributes to the neuronal soma. There are many accompanying pathologies in AD including cerebral amyloid angiopathy (accumulation of amyloid in the cerebrovasculature) and neuroinflammation (microglial and astrocytic reactivity to the abnormal proteins in the Alzheimer brain). These likely play a significant role in the disease progression. The amyloid hypothesis of AD is based upon the pathologic characteristics and the genetics of the disease. Early onset-familial Alzheimer’s disease (FAD) is a rare, genetic form of the disease. To date, all genes known to cause FAD are involved in the production of A?, and therefore amyloid. These genes are the amyloid precursor protein (APP) gene, and the presenilin 1 (PS1) and presenilin 2 (PS2) genes. APP is a single membrane-spanning protein whose exact physiological function is unknown. However, data suggest that APP may be involved in synapse formation and stability, cell adhesion, memory and even possibly may act as a G-protein coupled receptor Rabbit Polyclonal to VAV1 (reviewed by [2]). APP can be cleaved by 3 enzymes; , ? and secretase. Cleavage by ? and produces the A? peptide; the length of which is determined by the -secretase cleavage. Under normal conditions an cleavage is the dominant cleavage, which produces non-amyloidogenic fragments (reviewed by [3]). The presenilins are highly conserved proteins with 8 transmembrane domains and are now known to be part of the -secretase complex. Both PS1 and PS2 are physiologically cleaved forming 2 polypeptides that may function in the control of apoptosis. It is also known that genetic deletion of presenilins is lethal due to alteration of Notch processing and signaling (reviewed by [4]). Very simply, the amyloid cascade hypothesis states Azilsartan (TAK-536) that deposition of A? in the brain is the precipitating factor that then results in tau hyperphosphorylation, aggregation and, ultimately, neurofibrillary tangles. Amyloid deposition and tau pathology are then thought to both contribute to neuronal degeneration, which results in the cognitive decline in AD [5]. In support of the amyloid hypothesis, all FAD.