The immunopathological appearance of active demyelinating lesions in established MS is uniform. Initial heterogeneity of demyelinating lesions in the earliest phase of MS lesion formation may disappear over time as different pathways converge in one general mechanism of demyelination. Consistent presence of complement, antibodies, and Fcgamma receptors in phagocytic macrophages suggests that antibody- and complement-mediated myelin phagocytosis is the dominant mechanism of demyelination in established MS.

Background: About hundred years ago, Oskar Fischer proposed that the senile plaques are the consequence of the deposition of a foreign substance that could induce an inflammatory response leading to an abnormal neuritic response of the surrounding neurons. Objectives: To show that the interest in inflammation in Alzheimer’s disease (AD) is not only an early event in the history of AD but that inflammation is also an early event in the pathogenesis of AD. Methods: Evaluation of the neuropathological, epidemiological and genetic evidence for a role of inflammation early in the pathogenesis of AD. Results: Neuropathological studies show presence of activated microglia and inflammation-related mediators in the cerebral neocortex of autopsied patients with a low Braak stage for AD pathology. Prospective population-based cohort studies indicate that higher serum levels of acute phase proteins predict dementia. On a genetic level, it was found that the production capacity of proinflammatory cytokines after stimulation with lipopolysaccharide (a process that is under strong genetic control) is higher in offspring with a parental history of late-onset AD. Conclusion: Neuropathological studies show that a neuroinflammatory response in the cerebral neocortex parallels the early stages of AD pathology and precedes the late stage, tau-related pathology. Epidemiological and genetic studies indicate that systemic markers of the innate immunity are risk factors for late-onset AD.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta amyloid (A ) protein and the formation of neurofibrillary tangles. In addition, there is an increase of inflammatory proteins in the brains of AD patients. Epidemiological studies, indicating that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing AD, have encouraged the study on the role of inflammation in AD. The best-characterized action of most NSAIDs is the inhibition of cyclooxygenase (COX). The expression of the constitutively expressed COX-1 and the inflammatory induced COX-2 has been intensively investigated in AD brain and different disease models for AD. Despite these studies, clinical trials with NSAIDs or selective COX-2 inhibitors showed little or no effect on clinical progression of AD.The expression levels of COX-1 and COX-2 change in the different stages of AD pathology. In an early stage, when low-fibrillar A deposits are present and only very few neurofibrillary tangles are observed in the cortical areas, COX-2 is increased in neurons. The increased neuronal COX-2 expression parallels and colocalizes with the expression of cell cycle proteins. COX-1 is primarily expressed in microglia, which are associated with fibrillar A deposits. This suggests that in AD brain COX-1 and COX-2 are involved in inflammatory and regenerating pathways respectively. In this review we will discuss the role of COX-1 and COX-2 in the different stages of AD pathology. Understanding the physiological and pathological role of cyclooxygenase in AD pathology may facilitate the design of therapeutics for the treatment or prevention of AD.

Choline containing phospholipids are essential for the integrity of the'cell'membrane. Minor changes in the lysophosphatidylcholine (lyso-PC)/phosphatidylcholine (PC) ratio may lead to neuronal damage and cell loss. Several studies have shown protein and lipid oxidation in Alzheimer's disease (AD) affected brain regions. Amyloid-beta peptides may induce free-radical oxidative stress which normally is counteracted by anti-oxidant defense mechanisms. We hypothesize that oxidation may lead to changed concentrations of choline containing phospholipids in cerebrospinal fluid (CSF) of AD patients, because of the susceptibility of the unsaturated acyl-chains of PC for oxidation. PC and lyso-PC were determined in CSF of AD patients (n=19) and subjects with subjective memory complaints without dementia (n=19) by tandem mass spectrometry. No differences in total PC concentrations were observed between both study groups. Furthermore, we could not demonstrate different concentrations of PC species containing linoleic acid and PC species containing arachidonic acid. Interestingly, lyso-PC concentrations tended to be lower while the lyso-PC/PC ratio was significantly decreased in CSF of AD patients compared to controls (0.36% versus 0.54%; P=0.017). A comparable decrease was found for the lyso-PC/PC ratio for PC containing linoleic acid (P=0.022) or arachidonic acid (P=0.010), respectively. The lower lyso-PC/PC ratio in CSF of patients with AD may reflect alterations in the metabolism of choline-containing phospholipids in the brain in AD, and suggests that PC species containing linoleic acid or arachidonic acid are equally involved.

Neuropathological studies have revealed the presence of a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) in Alzheimer's disease (AD) brains. These constituents of innate immunity are involved in several crucial pathogenic events of the underlying pathological cascade in AD, and recent studies have shown that innate immunity is involved in the etiology of late-onset AD. Genome-wide association studies have demonstrated gene loci that are linked to the complement system. Neuropathological and experimental studies indicate that fibrillar amyloid-β (Aβ) can activate the innate immunity-related CD14 and Toll-like receptor signaling pathways of glial cells for pro-inflammatory cytokine production. The production capacity of this pathway is under genetic control and offspring with a parental history of late-onset AD have a higher production capacity for pro-inflammatory cytokines. The activation of microglia by fibrillar Aβ deposits in the early preclinical stages of AD can make the brain susceptible later on for a second immune challenge leading to enhanced production of pro-inflammatory cytokines. An example of a second immune challenge could be systemic inflammation in patients with preclinical AD. Prospective epidemiological studies show that elevated serum levels of acute phase reactants can be considered as a risk factor for AD. Clinical studies suggest that peripheral inflammation increases the risk of dementia, especially in patients with preexistent cognitive impairment, and accelerates further deterioration in demented patients. The view that peripheral inflammation can increase the risk of dementia in older people provides scope for prevention.