Complement Activation in Very Early Alzheimer Disease

Abstract

The activation of the classical complement (C)-system in early-stage Alzheimer disease (AD) and nondemented aging was examined with immunohistochemistry in subjects assessed by the Clinical Dementia Rating (CDR). Activation (staining for C3 and C4 fragments) was found in all brains with amyloid deposits, including all nondemented (CDR 0) cases, with either small numbers of diffuse plaques or with sufficient plaques and tangles to indicate preclinical AD. Staining for C3 and C4 increased in parallel with plaque density in very mild to severe clinical AD. A subset of very mild AD (CDR 0.5) cases also showed C1q (on plaques) and C5b-9 (on neuritic plaques and tangles), whereas these C-fragments were consistently found in severe AD (CDR 3). Mirror section (split-face) analysis showed that C1q, C3, and apoJ (clusterin) occurred on the same plaques. However, C-system regulators CD59, CR1, DAF, and MCP were not detected on plaques or tangles at any stage, indicating that C-activation related to AD is incompletely controlled.

NF-κB and Enhancer-binding CREB Protein Scaffolded by CREB-binding Protein (CBP)/p300 Proteins Regulate CD59 Protein Expression to Protect Cells from Complement Attack

“…However, the downregulation of CD59 is also involved in the pathogenesis of many human diseases to different extents. Complement activation, such as by ␤-amyloid, plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer disease (24), and the degree of neuron damage has been positively correlated with the intensity of deposition of complement-activating products in plaques or tangles, especially SC5b-9; this phenomenon is most likely due to the undetectable expression of mCRPs, including CD59 (25,26). Therefore, it is reasonable to hypothesize that a CD59 deficiency may contribute to the pathogenesis of Alzheimer disease (27).…”

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

“…Aside from these peripheral blood cells, CR1 is also expressed on lymph node follicular dendritic cells, Langerhan cells in the skin and glomerula podocytes (Yoon and Fearon 1985;Liu and Niu 2009;Crehan et al 2012). Expression of CR1 has also been reported on human astrocytes (Gasque et al 1996) and neurons (Zanjani et al 2005;Hollingworth et al 2010), although elsewhere CR1 was not detected on these cells, and it was stated that CR1 expression in the brain was likely to be low, and potentially restricted to the phagocytic Kolmer cells of the choroid plexus (Singhrao et al 1999). In addition to the membrane confined versions of the protein, a soluble form of CR1 (sCR1) exists at low levels (~30ng/ml) in the blood (Yoon and Fearon 1985), as well as a form of the protein found in urine, thought to be derived from vesicles from glomerula podocytes ).…”

Unraveling the biological mechanisms in Alzheimer's disease — Lessons from genomics

“…and CLU in inflammation damage (Khera and Das, 2009;Zanjani et al, 2005) or PICALM in intracellular trafficking of synaptic vesicle proteins (Harel et al, 2008).…”