Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study

BACKGROUND: We aimed to investigate the influence of oligomeric forms of β-amyloid (Aβ) and the influence of the duration of exposure on the development of tau phosphorylation. METHODS: Aβ oligomers 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 Aβ oligomers had no effect on p-tau epitopes but did result in elevation of phosphorylated/activated GSK3 (pGSK3). Chronic infusion of Aβ 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 Aβ. Control experiments revealed that the infusion of Aβ 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 Aβ(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 Aβ production, may have enduring impact on the risk for tauopathy.