PD participated in the A?? staining. DD designed and carried out the brain sectioning, staining, and preparation of brain slices for the analyses. TG provided the mice and participated in the revision of the manuscript. All authors read and approved the final manuscript. Acknowledgements We thank Dr. David Borchelt for comments, suggestions, and corrections of previous drafts of the manuscript.
A selleck catalog role for inflammation in the pathogenesis of Alzheimer’s disease (AD) had been discussed even in the earliest days of AD research. A hundred years ago Oskar Fischer wrote that cerebral senile plaque formation could be considered as the result of an extracellular deposition of abnormal substance in the cortex that induces a local inflammatory reaction, followed by an aberrant regenerative response of the surrounding nerve fibers.

However, he was un-successful in his attempts to show the morphological characteristics of an inflammatory response around plaques and to detect complement proteins by performing complement-binding studies. Seventy years later, with the advent of monoclonal antibodies for immunohistochemistry, complement factors and clustering of activated microglia could be demonstrated within plaques [1]. After the discovery of amyloid-?? (A??) as the main constituent of senile plaques, the concept was formed that the A?? peptide itself can induce a local inflammatory response, which was supported by in vitro findings showing that fibrillar A?? can bind complement factor C1 and activate the classical complement pathway without involvement of antibodies [2].

The inflammatory process in AD brains is not restricted to just a single step of the pathological process; inflammation-related proteins are involved in several crucial pathogenic events of the underlying pathological cascade, such as A?? generation and clearance, gliosis and increased phosphorylation of tau with accelerated tangle formation [3,4]. It is important to keep in mind that inflammation itself has both beneficial effects, such as the phagocytosis of the toxic A?? fibrils, and detrimental effects on neighboring cells by prolonged elevation of pro-inflammatory mediators. Clinicopathological studies show that the presence of activated microglia and inflammation-related mediators in the cerebral neocortex of patients with a low Braak stage for AD pathology precedes extensive tau-related neurofibrillary pathology [5] (Figure ?(Figure1).

1). Clinical research using positron emission tomography with the peripheral benzodiazepine receptor ligand PK-11195 as a marker for activated microglia indicates that AV-951 activation of microglia precedes cerebral atrophy in AD patients [6]. A positron emission tomography study using the Pittsburg com-pound B for visualization of fibrillar www.selleckchem.com/products/Temsirolimus.html amyloid and the PK-11195 ligand for microglia activation showed that amyloid deposition with microglia activation can be detected in vivo in around 50% of patients with mild cognitive impairment [7].