The Neuroinflammatory Response in Plaques and Amyloid Angiopathy in Alzheimers Disease: Therapeutic Implications

Abstract

The amyloid plaques in Alzheimer's disease (AD) brains are co-localised with a broad variety of inflammation-related proteins (complement proteins, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the Abeta depositions in the neuroparenchyma are closely associated with a locally-induced, non-immune-mediated chronic inflammatory response. Clinicopathological and neuroradiological data show that activation of microglia are a relatively early pathogenic event that precedes the process of severe neuropil destruction in patients. Recent gene findings (cDNA microarray) confirm the immunohistochemical findings of an early involvement of inflammatory and regenerative pathways in AD pathogenesis. Abeta deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mice models harbouring the pathological AD mutations, while "later" neurodegenerative characteristics are not seen in these models. Next to the plaques, Abeta amyloid deposition is frequently found in the walls of cerebral vessels (cerebral amyloid angiopathy). Most common is the type of amyloid deposition in the walls of meningeal and medium-sized cortical arteries, and more rarely, microcapillary amyloid angiopathy (dyshoric angiopathy). Immunohistochemical studies show that in AD patients, the majority of the amyloid deposits in the walls of the larger vessels is not associated with a chronic inflammatory response in contrast to micro-capillary amyloid angiopathy. In this contribution, we will give an overview of the similarities and differences between the involvement of inflammatory mechanisms in vascular and plaque amyloid in AD and transgenic models. The implications of the reviewed studies for an inflammation-based therapeutical approach in AD will be discussed.

Multiple Low-Dose Infusions of Human Umbilical Cord Blood Cells Improve Cognitive Impairments and Reduce Amyloid-β-Associated Neuropathology in Alzheimer Mice

“…2g). This reflects the widely accepted notion of an upregulation of Ab 40 and Ab 42 early on in AD. Further, cognitive decline robustly connects with this elevation of Ab 40 and Ab 42 .…”

“…2a, b) and insoluble (Fig. 2c, d) Ab 40 and Ab 42 . A t-test revealed a significant difference in the cerebral parenchyma regions between HUCBC-infused versus PBS-treated mice.…”

“…Further, cognitive decline robustly connects with this elevation of Ab 40 and Ab 42 . Indeed, cognitive degeneration [33,34] has been associated with the long and the most toxic isoform of Ab, Ab 42 , and this isoform has also been shown to elicit a strong proinflammatory immunological response in the brain [18].…”

“…It has been shown that Ab peptides mediate proinflammatory and neurodegenerative changes and oligomeric forms of the peptide are neurotoxic as well as synapse toxic [39]. Indeed, it is well established that brain inflammatory mechanisms mediated by reactive glia are activated in response to Ab plaques [40][41][42] and these changes could negatively affect cognitive function.…”

“…These analyses show decreased levels of both soluble (a, b) and insoluble (c, d) Ab 40 and Ab 42 in brain homogenates prepared from PSAPP/ HUCBC mice in both 6-and 10-month treatment groups when compared with PSAPP/PBS controls [n = 10 (5\/5_)]. A t-test revealed a significant difference between PBS-injected and HUCBC-infused conditions, in both soluble Ab 40,42 and insoluble Ab 40,42 [n = 10 (5\/5_)]. Ab species and b-CTF were analyzed in mouse brain homogenates from (e) 6-month treatment and (f) 10-month treatment group using monoclonal Ab 1-16 antibody (6E10).…”