CYTOKINES IN THE BRAIN Glia-derived cytokines and the biogenesis of amyloid plaques in Alzheimer's disease

ondly AD is the commonest form of dementia in the measurement of ChAT activity. 11 The results are expressed as aging population. The disease is characterised by the a percentage of the control values. Each bar represents the formation of amyloid plaques and neurofibrillary mean value of six estimations ± s.e.m. In comparison with tangles, and it is believed that one or both of these controls, amounts of NGF, bFGF and TGF-b were significantly abnormalities cause progressive death of nerve cells. 1 increased and ChAT activity was markedly decreased in AD. In the past, the majority of investigations have therefore focused on the accumulation of amyloid b-protein (Ab) and the paired helical filaments, and very little tein (APP) metabolism thereby facilitating plaque attention has been paid to changes in the metabolism of formation. To investigate the possible sequence of glial cells, which surround neuritic plaques throughout events in the latter scenario further analyses were made their development. Studies on postmortem brains from of the production of cytokines in reactive glial cells, AD patients have revealed marked increases in the lev- the effects of these cytokines on the metabolism of the els of cytokines or growth factors. The amounts of different APP isoforms, and the effects of Ab peptide nerve growth factor (NGF), basic fibroblast growth fac- on synthesis and secretion of cytokines in glial cells. tor (bFGF) and transforming growth factor-b (TGF-b) A number of cytokines, including bFGF, TGF-b, are increased by about 50%, 110% and 80%, respect- interleukin-1 (IL-1), IL-6, are markedly increased in the ively and choline acetyltransferase (ChAT) activity is brain after injury, presumably as part of a specific prodecreased by about 70% in AD temporal cortex tective response mechanism. The reactive astrocytes (Figure 1), with no major changes in the pharmacoki- and microglia are responsible for the increases in these netics of their receptors. 2‐5 Immunocytochemical stud- cytokines. 5,10,11 However, the elevation in expression ies have shown that the elevation of cytokines is of IL-1, IL-6 and tumour necrosis factor-a has been mainly in glial cells associated with plaques. 3,5‐9 Since observed within 6‐8 h after brain injury, and mRNA some of these cytokines support the survival of neu- for IL-1b is induced within 15 min of forebrain ischaerons in culture, this raises a number of questions, mia. 10,12 This would indicate that the localized synincluding whether the cytokines are related to the dis- thesis of cytokines at the site of brain injury propagates ease process or are simply secondary to cell injury, and the microglia and astrocyte reactions in an autocrine what role they play in the development of the disease. manner, which in turn will increase cytokine proTo account for these findings, we proposed that in AD duction.