Chemotherapy promotes astrocytic response to Aβ deposition, but not Aβ levels, in a mouse model of amyloid and APOE

Many cancer survivors experience cancer-related cognitive impairment (CRCI), which is characterized by problems of attention, working memory, and executive function following chemotherapy and/or hormonal treatment. APOE4, the strongest genetic risk factor for Alzheimer's Disease (AD), is also a risk factor for CRCI, especially among survivors exposed to chemotherapy. We explored whether the effects of APOE genotype to chemotherapy were associated with an increase in AD pathological processes, using a mouse model of amyloid (5XFAD) along with the E3 or E4 alleles of human APOE (E3FAD and E4FAD). Six-month-old female E3FAD mice (control n = 5, treated n = 5) and E4FAD (control n = 6, treated n = 6) were treated with two doses of doxo-rubicin (total 10 mg/kg) or DMSO vehicle. After six weeks, mice were euthanized and brains were analyzed by immunohistochemistry and biochemical assays. Doxorubicin-treated mice had the same level of A beta in the brain as control mice, as measured by 6E10 immunohistochemistry, A beta 40 and A beta 42 ELISAs, and plaque morphologies. Doxorubicin significantly increased the level of the astrocytic response to A beta deposits, which was independent of APOE genotype; no effects of doxorubicin were observed on the microglial responses. These data are consistent with a model in which the effects of doxorubicin on risk of CRCI are unrelated amyloid accumulation, but possibly related to glial responses to damage.

Automated summary

Many cancer survivors experience cancer-related cognitive impairment (CRCI), with the APOE4 gene being a risk factor. Research found that the effects of doxorubicin on the brain of mice may not be related to amyloid accumulation, but possibly associated with astrocytic responses to damage.