Amyloid Associated Proteins in Alzheimers and Prion Disease

Abstract

Clustering of activated microglia in Abeta deposits is related to accumulation of amyloid associated factors and precedes the neurodegenerative changes in AD. Microglia-derived pro-inflammatory cytokines are suggested to be the driving force in AD pathology. Inflammation-related proteins, including complement factors, acute-phase proteins, pro-inflammatory cytokines, that normally are locally produced at low levels, are increasingly synthesized in Alzheimer's disease (AD) brain. Similar to AD, in prion diseases (Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease and experimentally scrapie infected mouse brain) amyloid associated factors and activated glial cells accumulate in amyloid deposits of conformational changed prion protein (PrPres). Biological properties of Abeta and prion (PrP) peptides, including their potential to activate microglia, relate to Abeta and PrP peptide fibrillogenic abilities that are influenced by certain amyloid associated factors. However, since small oligomers of amyloid forming peptides are more toxic to neurons than large fibrils, certain amyloid associated factors that enhance fibril formation, may sequester the potentially harmful Abeta and PrP peptides from the neuronal microenvironment. In this review the positive and negative actions of amyloid associated factors on amyloid peptide fibril formation and on the fibrillation state related activation of microglia will be discussed. Insight in these mechanisms will enable the design of specific therapies to prevent neurodegenerative diseases in which amyloid accumulation and glial activation are prominent early features.

Serum Amyloid P Component as a Biomarker in Mild Cognitive Impairment and Alzheimer’s Disease

“…Despite the increased synthesis of SAP in AD brains as shown by McGeer et al [31] , we were unable to detect an increase in CSF SAP levels in AD and MCI cases compared to controls [31] . Possibly CSF SAP levels are not only dependent on the intraparenchymal synthesis, but also on accumulation in A ␤ plaques [17,19] and diffusion or transport across the blood-brain barrier; a subject for further study. Only three cross-sectional studies investigating CSF SAP levels in AD and controls have been reported (as summarized in table 3 ).…”

“…SAP binding to newly formed amyloid fibrils may protect the A ␤ deposits from proteolysis, and as a consequence promote A ␤ fibril and amyloid plaque formation in the brain [11,[13][14][15][16] . Clustering of activated microglial cells in A ␤ plaques was observed in SAP-and C1q-containing A ␤ plaques preceding tau-related neurodegenerative changes [17] . In vitro, SAP and C1q inhibit the microglial uptake of A ␤ [18] .…”

“…In vitro, SAP and C1q inhibit the microglial uptake of A ␤ [18] . This inability to remove A ␤ in the presence of SAP and C1q may explain the observed enhancement by SAP and C1q of the A ␤ -mediated activation of microglia in vitro [17,19] . In addition, SAP can also have a direct effect on neuronal cells, as SAP was shown to induce apoptosis in neuronal cells in vitro as well as in vivo [20] .…”

Role of Cyclin-Dependent Kinase 5 in the Neurodegenerative Process Triggered by Amyloid-Beta and Prion Peptides: Implications for Alzheimer’s Disease and Prion-Related Encephalopathies

“…Since AD and PRE share analogous clinical and neuropathological characteristics (Aguzzi and Haass 2003;Veerhuis et al 2005;Barnham et al 2006), in the present work, we perform a comparative study, using Ab and PrP synthetic peptides in order to determine the involvement of Cdk5 in tau phosphorylation and neuronal death under AD and PRE conditions. Using the selective Cdk5 inhibitor roscovitine, we observed that, when Cdk5 is not active, there is a significant reduction in the neuronal apoptotic death caused by PrP 106-126 or Ab 1-40 (Fig.…”

Cellular Prion Protein and Sexual Dimorphic Areas in Rodents. Correlates with Alzheimer Disease

“…The relationship between the PrPC and physiopathological mechanisms of Alzheimer's disease (AD) is well understood [23][24][25][26][27][28][29]. On our part, we have observed a particular behaviour of PrPC in brains with AD.…”