Amyloid Oligomers Exacerbate Tau Pathology in a Mouse Model of Tauopathy

作者：Selenica Maj Linda B; Brownlow Milene; Jimenez Jeffy P; Lee Daniel C; Pena Gabriela; Dickey Chad A; Gordon Marcia N; Morgan Dave^*

来源：Neurodegenerative Diseases, 2013, 11(4): 165-181.

DOI：10.1159/000337230

• beta-Amyloid
• Glycogen synthase kinase 3 alpha/beta
• Inflammation
• Microglia
• Microosmotic pump
• Phosphorylation
• Tau

Background: We aimed to investigate the influence of oligomeric forms of beta-amyloid (A beta) and the influence of the duration of exposure on the development of tau phosphorylation. Methods: A beta oligonners were injected intracranially either acutely into 5-month-old rTg4510 mice and tissue was collected 3 days later, or chronically into 3-month-old mice and tissue was collected 2 months later. Several forms of phosphorylated tau (p-tau), GSK3 (glycogen synthase kinase-3) and microglial and astrocyte activation were measured. Results: Acute injections of A beta oligorners had no effect on p-tau epitopes but did result in elevation of phosphorylated/activated GSK3 (pGSK3). Chronic infusion of A beta oligomers into the right hippocampus resulted in 3- to 4-fold elevations in several p-tau isoforms with no changes in total tau levels. A significant elevation in pGSK3 accompanied these changes. Microglial staining with CD68 paralleled the increase in tau phosphorylation, however, CD45 staining was unaffected by A beta. Control experiments revealed that the infusion of A beta from the minipumps was largely complete by 10 days after implantation. Thus, the elevation in p-tau 2 months after implantation implies that the changes are quite persistent. Conclusion: Soluble A beta(1-42) oligomers have long-lasting effects on tau phosphorylation in the rTg4510 model, possibly due to elevations in GSK3. These data suggest that even brief elevations in A beta production, may have enduring impact on the risk for tauopathy.

• 出版日期2013