The pathological cascade of Alzheimer's disease: the role of inflammation and its therapeutic implications.
Alzheimer's disease is a chronic neurodegenerative disease causing progressive impairment of memory and other cognitive functions. A number of sequential events are suggested to be associated with different pathological aspects observed in Alzheimer's disease, the so-called amyloid cascade hypothesis. Mismetabolism of the beta-amyloid precursor protein, as a result of mutations in the amyloid precursor protein gene or as results of impaired cleavage, leads to the formation of nonfibrillar and fibrillar amyloid-beta deposits. Glial cells are attracted to and activated by these amyloid-beta deposits. After activation, these cells secrete inflammatory mediators and reactive oxygen species, which can aggravate the aggregation of amyloid-beta. Some of the products released by activated glial cells, as well as amyloid-beta itself, can induce or promote neurodegeneration. Several mechanisms, such as mitotic reentry, apoptosis and cytoskeletal changes are suggested to be involved in neuronal loss. This review will outline several pathological mechanisms in Alzheimer's disease as well as some means of therapeutic intervention following the amyloid cascade hypothesis.
Hoozemans
Jeroen J M
JJ
Department of Pathology, Graduate School of Neurosciences Amsterdam, Research Institute Neurosciences Vrije Universiteit, VU University Medical Center, The Netherlands. jjm.hoozemans@vumc.nl
Veerhuis
Robert
R
Rozemuller
Annemieke J M
AJ
Eikelenboom
Piet
P
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology*; D018836:Inflammation Mediators / Q000502:physiology; D009410:Nerve Degeneration / Q000473:pathology; D009457:Neuroglia / Q000473:pathology; D058225:Plaque, Amyloid / Q000473:pathology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators