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Page 26
allied
academies
13
th
International Conference on
Alzheimers Disease and Dementia
November 25-26, 2019 | Frankfurt, Germany
Journal of Psychology and Cognition | Volume: 04
J Psychol Cognition, Volume: 04
A novel apolipoprotein E antagonist functionally blocks apolipoprotein E Interaction
withN-terminal Amyloid precursor protein, Reduces β-Amyloid-Associated Pathology
and improves cognition
Darrell Sawmiller
University of South Florida, USA
T
he E4 isoform of apolipoprotein E (apoE4) is a major
genetic risk factor for the development of sporadic
Alzheimer’s disease (AD) and its modification has been
an intense focus for treatment of AD in recent years. We
investigated the binding of apoE, a peptide corresponding
to its low density lipoprotein receptor (LDRL) binding
domain (aa 133-152, ApoEp) and modified ApoEp to
amyloid precursor protein (APP) and their effects on Aβ
production in cultured cells. Having discovered a peptide
which blocks the interaction of apoE with N-terminal APP,
we investigated the effects of this peptide and ApoEp
on AD-like pathology and behavioral impairment in 3XTg
and 5XFAD transgenic mice. ApoE and ApoEp, but not
truncated apoE lacking the LDLR binding domain, physically
interacted with N-terminal APP and thereby mediated Aβ
production. Interestingly, the addition of six lysine residues
to the N-terminal ApoEp (6KApoEp) directly inhibited
apoE binding to N-terminal APP and markedly limited
apoE- and ApoEp-mediated Aβ generation, presumably
through decreasing APP cellular membrane trafficking and
p44/42 mitogen-activated protein kinase phosphorylation.
Moreover, while promoting apoE interaction with APP
by ApoEp exacerbated Aβ and tau brain pathologies in
3XTg-AD mice, disrupting this interaction by 6KApoEp
ameliorated cerebral Aβ and tau pathologies, neuronal
apoptosis, synaptic loss, and hippocampal-dependent
learning and memory impairment in 5XFAD mice without
altering cholesterol, LDLR, and apoE expression levels.
These data suggest that disrupting apoE interaction
with N-terminal APP may be a novel disease-modifying
therapeutic strategy for AD.
e:
jtan@health.usf.eduNotes: