Inflammatory Response in the Hippocampus of PS1M146L/APP751SLMouse Model of Alzheimer's Disease: Age-Dependent Switch in the Microglial Phenotype from Alternative to Classic

“The soluble fractions (S1) were obtained by ultracentrifugation of the homogenates as described previously (Kayed et al., 2003).”

“The software calculated the estimated total number of cresyl-violet stained nuclei in the CA1 region using the optical fractionator formula (West et al., 1991; Schmitz and Hof, 2005), N 1/bsf.1/ssf.1/asf.1/hsf.”

“The recruitment of CD4 Th1-cells in experimental autoimmune encephalomyelitis (EAE; a disease similar to human multiple sclerosis) induced the production of, among other cytotoxic factors, TNF- (Dhib-Jalbut et al., 2006; Weaver et al., 2007).”

“…reported that aging and/or A could decrease the neuronal expression of microglial inhibitory factors, such as CD200, fractalkine or neurotransmitters (Acetylcholine or noradrenaline) (Cardona et al., 2006; Chitnis et al., 2007; Heneka and O’Banion, 2007; Lyons et al., 2007a; Duan et al., 2008).”

“The precision of the individual estimations is expressed by the coefficient of error (CE) (Gundersen et al., 1999) and here we have estimated the total CE (CE group value) that was calculated using the CEs in each individual animal.”

“As proposed by the inflammation hypothesis of Alzheimer’s disease (AD), the neurodegenerative process could be exacerbated by a chronic inflammatory response to -amyloid (A ) peptides (for review, see Griffin et al., 1998; Wyss-Coray, 2006; Heneka and O’Banion, 2007).”

“We observed a close spatial and temporal parallelism between A deposits and microglial activation (Simard et al., 2006).”

“These ADDLs were exclusively present in AD patients (Gong et al., 2003; Lacor et al., 2004) and their content increased with the disease severity (Lambert et al., 2007).”

“Thus, according with recent in vivo observations (Meyer-Luehmann et al., 2008), plaques attracted and stimulated microglial cells.”

“These ADDLs were exclusively present in AD patients (Gong et al., 2003; Lacor et al., 2004) and their content increased with the disease severity (Lambert et al., 2007).”

“…the decrease in the early recruitment of the microglial cells, by genetic ablation of either TLR2 receptor, in a PS1/APP model (Richard et al., 2008) or CCR2 in Tg2576 (El Khoury et al., 2007), increased A 42 levels, accelerated memory impairments and increased vascular amyloid pathology.”

“It is well known that diffusible aggregated A forms (ADDLs/oligomers) are highly toxic (De Felice et al., 2007).”

“We determined the expression of YM-1 and Arg-1 genes, considered markers of the alternative differentiation in peripheral macrophages (Edwards et al., 2006).”

“As proposed by the inflammation hypothesis of Alzheimer’s disease (AD), the neurodegenerative process could be exacerbated by a chronic inflammatory response to -amyloid (A ) peptides (for review, see Griffin et al., 1998; Wyss-Coray, 2006; Heneka and O’Banion, 2007).”

“As proposed by the inflammation hypothesis of Alzheimer’s disease (AD), the neurodegenerative process could be exacerbated by a chronic inflammatory response to -amyloid (A ) peptides (for review, see Griffin et al., 1998; Wyss-Coray, 2006; Heneka and O’Banion, 2007).”

“The software calculated the estimated total number of cresyl-violet stained nuclei in the CA1 region using the optical fractionator formula (West et al., 1991; Schmitz and Hof, 2005), N 1/bsf.1/ssf.1/asf.1/hsf.”

“Activated inflammatory cells could mediate neuronal damage by producing toxic products, such as inflammatory cytokines, excitatory amino acids, reactive oxygen intermediates and other factors (Mrak and Griffin, 2005; Craft et al., 2006; Ralay Ranaivo et al., 2006; Zipp and Aktas, 2006).”

“In this sense, Bolmont et al. (2008) have recently demonstrated the internalization of A peptides by plaque-associated microglia and proposed an active role in the maintenance of plaque size.”

“This potential cytotoxic effect was further emphasized by clinical studies demonstrating that the symptoms of AD could be attenuated by nonsteroidal antiinflammatory drugs (Aisen, 2000; McGeer and McGeer, 2007).”

“According with previous reports in AD and AD models (Itagaki et al., 1988; Togo et al., 2002; Stalder et al., 2005) we observed CD3-cells in 18-month-old PS1xAPP hippocampus.”

“, 2007a,b) and enhanced A phagocytosis (Koenigsknecht-Talboo and Landreth, 2005).”

“Multiple in vitro reports have probed the influence of IL-4 in the development of a non-proinflammatory alternative phenotype (Iribarren et al., 2005; Butovsky et al., 2005; Ponomarev et al., 2007; Lyons et al., 2007a,b).”

“In presence of IL-4, microglia produces growth factors (i.e., IGF-1) (Butovsky et al., 2006; Zhao et al., 2006).”

“However, recent trials have not confirmed this positive effect (Aisen et al., 2003; Reines et al., 2004).”

“Multiple in vitro reports have probed the influence of IL-4 in the development of a non-proinflammatory alternative phenotype (Iribarren et al., 2005; Butovsky et al., 2005; Ponomarev et al., 2007; Lyons et al., 2007a,b).”

“Activated inflammatory cells could mediate neuronal damage by producing toxic products, such as inflammatory cytokines, excitatory amino acids, reactive oxygen intermediates and other factors (Mrak and Griffin, 2005; Craft et al., 2006; Ralay Ranaivo et al., 2006; Zipp and Aktas, 2006).”

“form the ADDLs (Lambert et al., 2001), we diluted the 5 mM DMSO”

“The observed 6E10-positive bands corresponded with the reported Mr for the oligomeric A forms, detected by Western blots (see Lambert et al., 2007), and also similar to soluble oligomers identified in other aged tg models (Lesné et al., 2006).”

“In this sense, vaccination against the A peptides led to activation of microglia and successfully decreased amyloid load (Wilcock et al., 2003, 2004a,b).”

“Furthermore, the decrease in the early recruitment of the microglial cells, by genetic ablation of either TLR2 receptor, in a PS1/APP model (Richard et al., 2008) or CCR2 in Tg2576 (El Khoury et al., 2007), increased A 42 levels, accelerated memory impairments and increased vascular amyloid…”

“The neuronal toxicity to TNF- , TNF- related factors and iNOS has been extensively probed (Cantarella et al., 2003; Lee et al., 2004; Li et al., 2004; Medeiros et al., 2007; Uberti et al., 2007).”

“The generation and initial characterization of the PS1M146L (PS1) and PS1xAPP751sl (PS1xAPP) tg mice have been reported previously (Blanchard et al., 2003).”

“However, despite the age-dependent accumulation of extracellular A (Blanchard et al., 2003; Ramos et al., 2006; Caballero et al., 2007), no significant pyramidal degeneration was detected until 17–18 months of age (Schmitz et al., 2004; Ramos et al., 2006; unpublished results).”

“According with previous reports in AD and AD models (Itagaki et al., 1988; Togo et al., 2002; Stalder et al., 2005) we observed CD3-cells in 18-month-old PS1xAPP hippocampus.”

“, 2006), as well as neuroprotective factors that may protect against AD pathology (Streit, 2005).”

“…reported that aging and/or A could decrease the neuronal expression of microglial inhibitory factors, such as CD200, fractalkine or neurotransmitters (Acetylcholine or noradrenaline) (Cardona et al., 2006; Chitnis et al., 2007; Heneka and O’Banion, 2007; Lyons et al., 2007a; Duan et al., 2008).”

“In this sense, vaccination against the A peptides led to activation of microglia and successfully decreased amyloid load (Wilcock et al., 2003, 2004a,b).”

“Neuroinflammation is a key feature of AD pathology (Meda et al., 2001; Dudal et al., 2004; Craft et al., 2006).”

“However, despite the age-dependent accumulation of extracellular A (Blanchard et al., 2003; Ramos et al., 2006; Caballero et al., 2007), no significant pyramidal degeneration was detected until 17–18 months of age (Schmitz et al., 2004; Ramos et al., 2006; unpublished results).”

“According with previous reports in AD and AD models (Itagaki et al., 1988; Togo et al., 2002; Stalder et al., 2005) we observed CD3-cells in 18-month-old PS1xAPP hippocampus.”

“Although SDS-PAGE is a reductive technique and as such cannot provide an accurate reflection of the noncovalently associated A oligomers (Hepler et al., 2006), the presence of the soluble oligomeric A forms was also assayed in Western blots using 6E10.”

“The neuronal toxicity to TNF- , TNF- related factors and iNOS has been extensively probed (Cantarella et al., 2003; Lee et al., 2004; Li et al., 2004; Medeiros et al., 2007; Uberti et al., 2007).”

“In presence of IL-4, microglia produces growth factors (i.e., IGF-1) (Butovsky et al., 2006; Zhao et al., 2006).”

“Similarly, stimulating the immune system with lypopolisaccharide (LPS) led to a reduction in A plaques (DiCarlo et al., 2001; Herber et al., 2004).”

“…reported that aging and/or A could decrease the neuronal expression of microglial inhibitory factors, such as CD200, fractalkine or neurotransmitters (Acetylcholine or noradrenaline) (Cardona et al., 2006; Chitnis et al., 2007; Heneka and O’Banion, 2007; Lyons et al., 2007a; Duan et al., 2008).”

“Neuroinflammation is a key feature of AD pathology (Meda et al., 2001; Dudal et al., 2004; Craft et al., 2006).”

“The neuronal toxicity to TNF- , TNF- related factors and iNOS has been extensively probed (Cantarella et al., 2003; Lee et al., 2004; Li et al., 2004; Medeiros et al., 2007; Uberti et al., 2007).”

“Activated inflammatory cells could mediate neuronal damage by producing toxic products, such as inflammatory cytokines, excitatory amino acids, reactive oxygen intermediates and other factors (Mrak and Griffin, 2005; Craft et al., 2006; Ralay Ranaivo et al., 2006; Zipp and Aktas, 2006).”

“Furthermore, damaged neurons could release microglial stimulants, such as ATP, UDP or CCL21 (de Jong et al., 2005; Inoue et al., 2007).”

“…reported that aging and/or A could decrease the neuronal expression of microglial inhibitory factors, such as CD200, fractalkine or neurotransmitters (Acetylcholine or noradrenaline) (Cardona et al., 2006; Chitnis et al., 2007; Heneka and O’Banion, 2007; Lyons et al., 2007a; Duan et al., 2008).”

“Neuroinflammation is a key feature of AD pathology (Meda et al., 2001; Dudal et al., 2004; Craft et al., 2006).”

“Furthermore, damaged neurons could release microglial stimulants, such as ATP, UDP or CCL21 (de Jong et al., 2005; Inoue et al., 2007).”

“The neuronal toxicity to TNF- , TNF- related factors and iNOS has been extensively probed (Cantarella et al., 2003; Lee et al., 2004; Li et al., 2004; Medeiros et al., 2007; Uberti et al., 2007).”

“The recruitment of CD4 Th1-cells in experimental autoimmune encephalomyelitis (EAE; a disease similar to human multiple sclerosis) induced the production of, among other cytotoxic factors, TNF- (Dhib-Jalbut et al., 2006; Weaver et al., 2007).”

“…reported that aging and/or A could decrease the neuronal expression of microglial inhibitory factors, such as CD200, fractalkine or neurotransmitters (Acetylcholine or noradrenaline) (Cardona et al., 2006; Chitnis et al., 2007; Heneka and O’Banion, 2007; Lyons et al., 2007a; Duan et al., 2008).”

“Western blots were performed as described previously (Araujo et al., 1996).”

“The neuronal toxicity to TNF- , TNF- related factors and iNOS has been extensively probed (Cantarella et al., 2003; Lee et al., 2004; Li et al., 2004; Medeiros et al., 2007; Uberti et al., 2007).”

“Multiple in vitro reports have probed the influence of IL-4 in the development of a non-proinflammatory alternative phenotype (Iribarren et al., 2005; Butovsky et al., 2005; Ponomarev et al., 2007; Lyons et al., 2007a,b).”

“The induction of iNOS expression by astrocytes, because of TNF- and/or TRAIL, has been previously reported (Akama and Van Eldik, 2000; Cantarella et al., 2008).”

“This potential cytotoxic effect was further emphasized by clinical studies demonstrating that the symptoms of AD could be attenuated by nonsteroidal antiinflammatory drugs (Aisen, 2000; McGeer and McGeer, 2007).”

“However, despite the age-dependent accumulation of extracellular A (Blanchard et al., 2003; Ramos et al., 2006; Caballero et al., 2007), no significant pyramidal degeneration was detected until 17–18 months of age (Schmitz et al., 2004; Ramos et al., 2006; unpublished results).”

“However, recent trials have not confirmed this positive effect (Aisen et al., 2003; Reines et al., 2004).”

“With aging, A β - depositing mice increase in the expression of alternative activation state genes and deactivation state genes at the expense of classical activation state genes 220 , however see also 221 .”

“seems to maintain even at relative old ages, suggesting that activated microglia surrounding Aβ plaques adopted an alternative phenotype, regardless of the age [92].”

“[132] observed at 6 months, when Aβ begins to accumulate in the APP/ PS1 Alzheimer’s disease mouse model, that there were YM1 cells present in the CNS; however, by 18 months YM1 mRNA levels decreased and there was a massive upregulation in inflammatory factors, suggesting a switch from M2 to M1 as pathology worsened […”