Table 1: “Bad” microglia in Alzheimer disease.

Publication(s)Type of StudyObservations

Wisniewski et al., 1989 [1], 1992 [2]; Frackowiak et al., 1992 [3]NeuropathologicMicroglia are “frustrated phagocytes” responsible for manufacture of amyloid fibrils and not for their removal.
Meda et al., 1995 [15]In vitroActivated microglia secrete proinflammatory cytokines that promote neural injury at high levels.
Tan et al., 1999 [16]Mouse modelsAβ and CD40L-stimulated microglia release TNF-α that injures primary cortical neurons. CD40 ligand-deficient Tg2576 mice have reduced microglial activation and tau hyperphosphorylation.
McGeer et al. 1990 [18], 1992 [19], 1996 [20]EpidemiologicThere is lower incidence of dementia in elderly patients with arthritis compared to the general population.
Mackenzie and Munoz, 1998 [21]NeuropathologicChronic NSAID users with senile plaques have 3-fold less activated microglia than non-users.
Szekely et al., 2004 [23]EpidemiologicSystematic review of over 25 epidemiologic studies shows ~50% reduced risk of AD associated with NSAID use.
Lim et al., 2000 [24], 2001 [72]Mouse modelsNSAID-treated Tg2576 mice have significantly reduced amyloid deposition, astrogliosis, and IL-1β abundance.
Jantzen et al., 2002 [25]; Yan et al., 2003 [26]; Heneka et al., 2005 [27]Mouse modelsIbuprofen-treated Tg2576, APP/PS1 or APPV717I transgenic mice have reduced microglial activation and amyloid deposits.
Tan et al., 2002 [30]Mouse modelsGenetic or pharmacologic ablation of CD40 ligand in Tg2576 mice reduces cerebral amyloidosis and mitigates gliosis.
Townsend et al., 2005 [31]In vitroCD40 ligand in the presence of Aβ (1–42) promotes a microglial proinflammatory antigen presenting cell phenotype.
Qiao et al., 2001 [32]Mouse modelsChronic intracerebroventricular injection of LPS accelerates Aβ plaque load in APPV717F transgenic mice.
Mori et al., 2010 [33]Mouse modelsForcing expression of proinflammatory S100B accelerates glial activation and cerebral amyloid pathology in Tg2576 mice.
Fuhrmann et al., 2010 [34]Mouse modelsCx3cr1 endorses microglial-mediated neuronal loss in 3xTg AD mice.
Lee et al., 2010 [36]Mouse modelsCx3cr1 deficiency reduces cerebral amyloid and reactive microglia in APP/PS1 and R1.40 mice. Cx3cr1−/− microglia have greater Aβ uptake.
Sundaram et al., 2012 [38]Mouse modelsNeuroinflammation occurs early and promotes neurodegeneration mediated by lysophosphatidylcholine and Cdk5/p25. Inducible p25 expression in vivo triggers neuroinflammation and intraneuronal Aβ.