Neuroinflammatory processes in Alzheimer’s disease

Abstract

Generation of neurotoxic amyloid beta peptides and their deposition along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer's disease (AD). Recent evidence suggests that inflammation may be a third important component which, once initiated in response to neurodegeneration or dysfunction, may actively contribute to disease progression and chronicity. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and inflammatory enzyme systems are expressed and released by microglia, astrocytes and neurons in the AD brain. Degeneration of aminergic brain stem nuclei including the locus ceruleus and the nucleus basalis of Meynert may facilitate the occurrence of inflammation in their projection areas given the antiinflammatory and neuroprotective action of their key transmitters norepinephrine and acetylcholine. While inflammation has been thought to arise secondary to degeneration, recent experiments demonstrated that inflammatory mediators may stimulate amyloid precursor protein processing by various means and therefore can establish a vicious cycle. Despite the fact that some aspects of inflammation may even be protective for bystander neurons, antiinflammatory treatment strategies should therefore be considered. Non-steroidal anti-inflammatory drugs have been shown to reduce the risk and delay the onset to develop AD. While, the precise molecular mechanism underlying this effect is still unknown, a number of possible mechanisms including cyclooxygenase 2 or gamma-secretase inhibition and activation of the peroxisome proliferator activated receptor gamma may alone or, more likely, in concert account for the epidemiologically observed protection.

The executioners sing a new song: killer caspases activate microglia

“…30 Further evidence demonstrating a link between Ab and neuroinflammation comes from studies performed in transgenic animals showing that cerebral amyloid deposition is increased under inflammatory conditions. 15 As mentioned above, a-synuclein appears to have a pivotal role in the pathogenesis of PD. For example, a-synuclein is the major protein component of Lewy bodies.…”

“…In the AD brain, microglia, astrocytes and neurons release various neuroinflammatory mediators, including complement activators and inhibitors, chemokines, cytokines and ROS. [13][14][15] Historically, inflammation was thought to be secondary to degeneration. However, compelling evidence suggests that inflammatory mediators might have a significant role in the pathogenesis of the disease.…”

“…Ab is toxic to neurons, which in turn activates microglia when they degenerate. 15 The activated microglia, in turn, are deleterious to neurons. 8 In addition, toxic Ab peptides show proinflammatory properties.…”

“…These cellular interactions fuel a self-propelling cycle that might drive progressive neurodegeneration in AD. 15 Health cost of neurodegenerative disorders associated with a microglia activation component. Neurodegenerative disorders have a tragic impact for those afflicted and their families.…”

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

“…In addition to producing proinflammatory cytokines, senescent microglia also express lipofuscin granules, higher levels of CD86, major histocompatibility complex II (MHC II), toll-like receptors (TLRs) and complement receptor 3 (CD11b) and display a decreased number and complexity of processes as described in activated microglia (Hanisch and Kettenmann, 2007;Tremblay et al, 2011). They also have reduced phagocytic activities of Aβ as demonstrated in aged transgenic mice (Heneka et al, 2010). The mechanisms involved in increased microglia activation in the ageing brain is not fully understood, although the impaired expression of CD200 and CX3CR1, known to be produced by neurons to maintain microglia in the non-activated state in the healthy brain, might be involved (Dilger and Johnson, 2008).…”