Cancer Chemotherapy Related Cognitive Impairment and the Impact of the Alzheimer’s Disease Risk Factor APOE

Fernandez, Harvey R.; Varma, Ashima; Flowers, Sarah A.; Rebeck, G. William

doi:10.3390/cancers12123842

Cited by 32 publications

(21 citation statements)

References 199 publications

(234 reference statements)

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“…However, even these behaviors provide opportunities for demonstrating how specific drugs or treatments may affect behavior in genotype‐specific ways within APOE mouse colonies. For example, we have reported that an anthracycline, doxorubicin, impaired Barnes Maze behavior only in APOE4 mice (Demby et al, 2020; Speidell et al, 2019), supporting the sensitivity of APOE4 individuals to cognitive impairment related to cancer chemotherapy (H. R. Fernandez et al, 2020; Grootendorst et al, 2005).…”

Section: Discussionmentioning

confidence: 85%

Independent APOE4 knock‐in mouse models display reduced brain APOE protein, altered neuroinflammation, and simplification of dendritic spines

Sepulveda

Luo

Nelson

et al. 2022

Journal of Neurochemistry

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APOE is an immunomodulator in the brain and the major genetic risk factor for late‐onset Alzheimer's disease (AD). Targeted replacement APOE mice (APOE‐TR) have been a useful tool to study the effects of APOE isoforms on brain neurochemistry and activity prior to and during AD. We use newly available APOE knock‐in mice (JAX‐APOE) to compare phenotypes associated with APOE4 across models. Similar to APOE4‐TR mice, JAX‐E4 mouse brains showed 27% lower levels of APOE protein compared with JAX‐E3 (p < 0.001). We analyzed several neuroinflammatory molecules that have been associated with APOE genotype. SerpinA3 was much higher in APOE4‐TR mice to APOE3‐TR mice, but this effect was not seen in JAX‐APOE mice. There were higher levels of IL‐3 in JAX‐E4 brains compared with JAX‐E3, but other neuroinflammatory markers (IL6, TNFα) were not affected by APOE genotype. In terms of neuronal structure, basal dendritic spine density in the entorhinal cortex was 39% lower in JAX‐E4 mice compared with JAX‐E3 mice (p < 0.001), again similar to APOE‐TR mice. One‐week treatment with ibuprofen significantly increased dendritic spine density in the JAX‐E4 mice, consistent with our previous finding in APOE‐TR mice. Behaviorally, there was no effect of APOE genotype on Barnes Maze learning and memory in 6‐month‐old JAX‐APOE mice. Overall, the experiments performed in JAX‐APOE mice validated findings from APOE‐TR mice, identifying particularly strong effects of APOE4 genotype on lower APOE protein levels and simplified neuron structure. These data demonstrate pathways that could promote susceptibility of APOE4 brains to AD pathological changes.

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Section: Discussionmentioning

confidence: 85%

Independent APOE4 knock‐in mouse models display reduced brain APOE protein, altered neuroinflammation, and simplification of dendritic spines

Sepulveda

Luo

Nelson

et al. 2022

Journal of Neurochemistry

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“…Apolipoprotein E (APOE), a complex glycolipoprotein that facilitates the uptake, transport, and distribution of cholesterol and other lipids, has been studied extensively in relation to cognitive functioning (16). The isoform ε4 has been associated with more pronounced cognitive decline with aging, following insult to the brain, and with a variety of disorders with prominent cognitive dysfunction (e.g., Alzheimer's disease, [16][17]. The isoform ε4's effect on cognitive decline is attributed to reduced neuronal and vascular repair, increased oxidative stress and in ammation, decreased production of neural progenitor cells, impairment of the blood brain barrier, and morphologic differences in brain structure (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

“…The isoform ε4 has been associated with more pronounced cognitive decline with aging, following insult to the brain, and with a variety of disorders with prominent cognitive dysfunction (e.g., Alzheimer's disease, [16][17]. The isoform ε4's effect on cognitive decline is attributed to reduced neuronal and vascular repair, increased oxidative stress and in ammation, decreased production of neural progenitor cells, impairment of the blood brain barrier, and morphologic differences in brain structure (17)(18)(19). APOE ε4 has been associated with poorer cognitive outcomes in patients with breast cancer and lymphoma (20)(21), testicular cancer (22) and brain tumors (23).…”

Section: Introductionmentioning

confidence: 99%

The impact of APOE and smoking history on cognitive function in older, long-term breast cancer survivors

et al. 2022

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To determine whether older breast cancer survivors score lower on neuropsychological tests compared to matched non-cancer controls and to test the hypotheses that survivors who were APOE ε4 carriers would have the lowest cognitive performance, but that smoking history would decrease the negative effect of ε4 on cognition. MethodsFemale breast cancer survivors who had been diagnosed and treated at age 60 or older and were 5 -15 year survivors (N=328) and age and education matched non-cancer controls (N=160) were assessed at enrollment and at 8, 16 and 24 month follow ups with standard neuropsychological and psychological assessments. Blood for APOE genotyping was collected and smoking history was assessed at enrollment. Participants were purposely recruited so that approximately 50% had a history of treatment with chemotherapy or no chemotherapy and approximately 50% had a smoking history. ResultsAfter adjusting for age, cognitive reserve, depression and fatigue, breast cancer survivors scored signi cantly lower on all domains of cognitive function. A signi cant two-way interaction demonstrated that the negative effect of ε4 on cognitive performance was stronger among survivors. A signi cant three-way interaction supported the hypothesis that smoking history had a protective effect on cognitive function in ε4 carriers that was more pronounced in the controls than the survivors. ConclusionsThe results support the long-term cognitive impact of breast cancer diagnosis and treatments on older, disease-free survivors, particularly for ε4 carriers. The results also emphasize the importance of assessing smoking history when examining APOE and cognition and are an example of the complex interactions of age, genetics, health behaviors and disease history in determining cognitive function.

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“…It also plays a crucial role in the maintenance of BBB, as well as in processes of oxidative stress, inflammation, and neuronal health. APOE can produce three alleles, but only the presence of APOE4 is considered as one of the possible risk factors for chemobrain development ( Fernandez et al, 2020 ). Cognitive impairment might occur regardless of used therapy, as it was observed in the cohort study on lymphoma and breast cancer survivors.…”

Section: Central Neurotoxicity: Chemobrainmentioning

confidence: 99%

Mechanisms of Chemotherapy-Induced Neurotoxicity

et al. 2022

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Since the first clinical trials conducted after World War II, chemotherapeutic drugs have been extensively used in the clinic as the main cancer treatment either alone or as an adjuvant therapy before and after surgery. Although the use of chemotherapeutic drugs improved the survival of cancer patients, these drugs are notorious for causing many severe side effects that significantly reduce the efficacy of anti-cancer treatment and patients’ quality of life. Many widely used chemotherapy drugs including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors, and thalidomide analogs may cause direct and indirect neurotoxicity. In this review we discuss the main effects of chemotherapy on the peripheral and central nervous systems, including neuropathic pain, chemobrain, enteric neuropathy, as well as nausea and emesis. Understanding mechanisms involved in chemotherapy-induced neurotoxicity is crucial for the development of drugs that can protect the nervous system, reduce symptoms experienced by millions of patients, and improve the outcome of the treatment and patients’ quality of life.

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Cancer Chemotherapy Related Cognitive Impairment and the Impact of the Alzheimer’s Disease Risk Factor APOE

Cited by 32 publications

References 199 publications

Independent APOE4 knock‐in mouse models display reduced brain APOE protein, altered neuroinflammation, and simplification of dendritic spines

Independent APOE4 knock‐in mouse models display reduced brain APOE protein, altered neuroinflammation, and simplification of dendritic spines

The impact of APOE and smoking history on cognitive function in older, long-term breast cancer survivors

Mechanisms of Chemotherapy-Induced Neurotoxicity

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