Alzheimer's disease (AD) is, at the neuropathological level, characterized by the accumulation and aggregation of misfolded proteins. The presence of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR) that may protect the cell against the toxic buildup of misfolded proteins. In this study we investigated the activation of the UPR in AD. Protein levels of BiP/GRP78, a molecular chaperone which is up-regulated during the UPR, was found to be increased in AD temporal cortex and hippocampus as determined by Western blot analysis. At the immunohistochemical level intensified staining of BiP/GRP78 was observed in AD, which did not co-localize with AT8-positive neurofibrillary tangles. In addition, we performed immunohistochemistry for phosphorylated (activated) pancreatic ER kinase (p-PERK), an ER kinase which is activated during the UPR. p-PERK was observed in neurons in AD patients, but not in non-demented control cases and did not co-localize with AT8-positive tangles. Overall, these data show that the UPR is activated in AD, and the increased occurrence of BiP/GRP78 and p-PERK in cytologically normal-appearing neurons suggest a role for the UPR early in AD neurodegeneration. Although the initial participation of the UPR in AD pathogenesis might be neuroprotective, sustained activation of the UPR in AD might initiate or mediate neurodegeneration.

No abstract

Alzheimer's disease (AD) and prion disease are characterized neuropathologically by extracellular deposits of A␤ and PrP amyloid fibrils, respectively. In both disorders, these cerebral amyloid deposits are co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase protein, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the cerebral A␤ and PrP deposits are closely associated with a locally induced, non-immunemediated chronic inflammatory response. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins, which are associated with A␤ plaques, are genetic risk factors for AD. Transgenic mice studies have established the role of amyloid associated acute-phase proteins in Alzheimer amyloid formation. In contrast to AD, there is a lack of evidence that cytokines and acute-phase proteins can influence disease progression in prion disease. Clinicopathological and neuroradiological studies have shown that activation of microglia is a relatively early pathogenetic event that precedes the process of neuropil destruction in AD patients. It has also been found that the onset of microglial activation coincided in mouse models of prion disease with the earliest changes in neuronal morphology, many weeks before neuronal loss and subsequent clinical signs of disease. In the present work, we review the similarities and differences between the involvement of inflammatory mechanisms in AD and prion disease. We also discuss the concept that the demonstration of a chronic inflammatorylike process relatively early in the pathological cascade of both diseases suggests potential therapeutic strategies to prevent or to retard these chronic neurodegenerative disorders. GLIA 40:232-239, 2002.

Future genetic studies need to identify genetic defects in at least two distinct familial forms of frontotemporal dementia (FTD) with unknown genetic defects: frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease.