Peripheral inflammation, apolipoprotein E4, and amyloid-β interact to induce cognitive and cerebrovascular dysfunction

Felecia M. Marottoli, Yuriko Katsumata, Kevin P. Koster, Riya Thomas, David W. Fardo, Leon M. Tai

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer’s disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 (APOE4), Amyloid-β (Aβ), and peripheral inflammation independently induce cerebrovascular damage, their collective effects remain to be elucidated. The goal of this study was to determine the interactive effect of APOE4, Aβ, and chronic repeated peripheral inflammation on cerebrovascular and cognitive dysfunction in vivo. EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aβ42 via expression of 5 Familial Alzheimer’s disease (5xFAD) mutations. Here, we utilized EFAD carriers [5xFAD+/-/APOE+/+ (EFAD+)] and noncarriers [5xFAD-/-/APOE+/+ (EFAD-)] to compare the effects of peripheral inflammation in the presence or absence of human Aβ overproduction. Low-level, chronic repeated peripheral inflammation was induced in EFAD mice via systemic administration of lipopolysaccharide (LPS; 0.5 mg/kg/wk i.p.) from 4 to 6 months of age. In E4FAD+ mice, peripheral inflammation caused cognitive deficits and lowered post-synaptic protein levels. Importantly, cerebrovascular deficits were observed in LPS-challenged E4FAD+ mice, including cerebrovascular leakiness, lower vessel coverage, and cerebral amyloid angiopathy-like Aβ deposition. Thus, APOE4, Ab, and peripheral inflammation interact to induce cerebrovascular damage and cognitive deficits.

Original languageEnglish
JournalASN Neuro
Issue number4
StatePublished - Aug 2017

Bibliographical note

Publisher Copyright:
© The Author(s) 2017.


  • Alzheimer’s disease
  • Apolipoprotein E4
  • Cerebrovasculature
  • Inflammation

ASJC Scopus subject areas

  • General Neuroscience
  • Clinical Neurology


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