Increase in the density of resting microglia precedes neuritic plaque formation and microglial activation in a transgenic model of Alzheimer's disease

Abstract

The formation of cerebral senile plaques composed of amyloid β peptide (Aβ) is a fundamental feature of Alzheimer's disease (AD). Glial cells and more specifically microglia become reactive in the presence of Aβ. In a triple transgenic model of AD (3 × Tg-AD), we found a significant increase in activated microglia at 12 (by 111%) and 18 (by 88%) months of age when compared with non-transgenic (non-Tg) controls. This microglial activation correlated with Aβ plaque formation, and the activation in microglia was closely associated with Aβ plaques and smaller Aβ deposits. We also found a significant increase in the area density of resting microglia in 3 × Tg-AD animals both at plaque-free stage (at 9 months by 105%) and after the development of A plaques (at 12 months by 54% and at 18 months by 131%). Our results show for the first time that the increase in the density of resting microglia precedes both plaque formation and activation of microglia by extracellular Aβ accumulation. We suggest that AD pathology triggers a complex microglial reaction: at the initial stages of the disease the number of resting microglia increases, as if in preparation for the ensuing activation in an attempt to fight the extracellular Aβ load that is characteristic of the terminal stages of the disease.

Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease

“…The presence of activated microglia has already been shown in the human AD brain (Itagaki et al, 1989) and in a mouse model of AD (Frautschy et al, 1998) and has been confirmed by other research groups in more recent studies (Bolmont et al, 2008;MeyerLuehmann et al, 2008;Rodriguez et al, 2010). Our µPET and immunohistochemistry results in the 15 months age group suggest the occurrence of neuroinflammation in the brains of APP/PS1 mice.…”

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

“…Furthermore, increased expression of proinflammatory cytokines has also been characterised in this model with increased mRNA expression of IL-1␤ and TNF-␣ apparent from eight months old (Hickman et al, 2008) and persisting up to 24 months old (Minogue et al, 2014). Similar evidence of neuroinflammation has been reported in the triple transgenic AD model with increased numbers of resting and activated microglia observed at nine and twelve months old respectively (Rodriguez et al, 2010) and increased mRNA expression of a panel of pro-inflammatory cytokines in 16 month old transgenic mice (Zaheer et al, 2013). There have also been data published surrounding the impact of an inflammatory environment on progression of disease pathology.…”

Physiology of Microglia

“…Surprisingly, the initiation of the activation program required a P2X 7 receptorassociated pore formation; in microglial cells transfected with a point mutant P2X 7 RG345Y (this mutant protein retains the channel function but cannot form the pore), microglial activation was significantly reduced (607). The P2X 7 receptors were also obligatory in mediating microglial activation in response to an intrahippocampal injection of A␤ protein (787); considering the pivotal role of microglial activation in AD-associated neuroinflammation (115,370,767), the P2X 7 receptors may be considered as important therapeutical targets.…”

“…It is well established that microglial cells accumulate at senile plaques in AD (370,767). The pattern recognition receptor CD36 initiates a signaling cascade that promotes microglial activation and chemotaxis to ␤-amyloid deposits in the brain (875).…”