Neuroinflammation in Alzheimer's disease and prion disease

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.

Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid β25–35-Induced Toxicity in Mice

“…These different species greatly differ in their neurotoxic potential and molecular mechanism mediating the toxicity. For instance, impairment of longterm potentiation (Walsh et al, 2002) and ER stress (Chafekar et al, 2007) may be mediated by small oligomers, whereas the neuroinflammatory response may rather involve fibrillar Ab (Eikelenboom et al, 2002). Preliminary observations of the laboratory showed that after in vitro aggregation, Ab [25][26][27][28][29][30][31][32][33][34][35] peptide exist in these different species including small oligomers, amorphous oligomers, and fibrillar forms (S Marchal, L Givalois, T Maurice, unpublished work).…”

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

“…The aggregation of Aß and ß-sheet formation are considered to be critical events that render these peptides neurotoxic (Pike et al, 1995). The presence of chronic neuroinflammation also contributes to the protracted degenerative course of AD (McGeer and McGeer, 1995), and it is also common to other neurodegenerative disorders, such as Parkinson's disease and Creutzfelt-Jacob disease (Eikelenboom et al, 2002;Gao et al, 2003). A chronic inflammatory response characterized by activated microglia, reactive astrocytes, complement factors, and increased inflammatory cytokine expression associated with Aß deposits has been described in the brain of AD patients (Rogers et al, 1996).…”

Modulation of connexin expression and gap junction communication in astrocytes by the gram‐positive bacterium S. aureus

“…However, the functional consequences resulting from changes in the extent of astrocyte coupling remain an area of debate and are likely influenced by the context of CNS damage (Farahani et al, 2005;Perez Velazquez et al, 2003). Neuroinflammation is a hallmark of various CNS pathologies such as trauma, bacterial meningitis, brain abscess, Alzheimer's disease, and multiple sclerosis, which share a general feature of reactive gliosis characterized, to varying degrees, by the proliferation and hypertrophy of activated astrocytes (Eikelenboom et al, 2002;Griffin and Mrak, 2002;Kielian, 2004;Koedel et al, 2002;McGeer and McGeer, 2002;Nau and Bruck, 2002;Scheld et al, 2002). When activated by an appropriate stimulus, astrocytes have the capacity to produce robust amounts of proinflammatory mediators which may have profound effects on GJC (Dong and Benveniste, 2001;Esen et al, 2004;Kim et al, 2005;Smits et al, 2001).…”