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alliedacademies
August 14-16, 2017 | Toronto, Canada
BRAIN DISORDERS AND DEMENTIA CARE
4th International Conference on
Neurosurg, an open access journal
ISSN: 2471-9633
The dynamic role of human induced pluripotent stem cell derived-astrocyte secreted APOE4 in
Alzheimer’s disease
Talitha Kerrigan
University of Bristol, UK
Alzheimer’s disease (AD) is the most prevalent
neurodegenerative condition worldwide. There are
currently an estimated 35 million AD sufferers, and this is
expected to double every 20 years so by 2050 there will be
round 115 million cases. Late onset AD (>age 65) makes up
the majority of cases, and the main contributing factor to the
rise in AD is increasing life expectancy. It is well established
that the human apolipoprotein E (APOE) gene is a strong
genetic risk factor for AD, specifically late onset. It encodes
one of 3 isoforms APOE2, -E3 and -E4, which vary only by 1 or
2 specific amino acids. However, this small change in peptide
sequence significantly modifies the protein conformation,
and results in isoform specific properties. The end result is
that different APOE isotypes modify the risk of developing
AD. Specifically APOE4 is associated with an increased risk
of AD. In the general population APOE3 is the most common
allele, and considered the ‘normal’ version of APOE ; yet over
65% of AD patients carry a copy of APOE4. Furthermore
APOE4, particularly when homozygous, is associated with a
lower age of onset of symptoms, usually 5-10 years compared
to the general population. The relationship between APOE
and AD is mainly attributed to the ability of the APOE protein
to bind Aβ. Astrocytes, one class of glial cells, are the most
abundant cells in the brain. Recent findings are implicating
non-cell-autonomous mechanisms of neurodegeneration
mediated by astrocytes. Astrocytes are vital for maintaining
normal homeostasis for the healthy brain, which is critical
for neuronal communication. How astrocyte activities
integrate into complex brain functioning, how they respond
to insult or injury and whether their responses promote or
inhibit repair is poorly understood. Therefore it is critical
to understand how to regulate astrocyte function in order
to benefit the treatment of neurodegenerative conditions.
In our lab, we are addressing the role of APOE in AD using
human induced pluripotent stem cells (iPSCs) derived from
patient donor skin cells; specifically the role of APOE in both
neurogenesis and astrocytic physiology, with particular focus
on astrocytic secreted APOE. Primarily, we have compared
the effects of the specific astrocyte secreted APOE isoform
(E4, E3) on health, maturation and physiology of neuronal
subtypes that are particularly susceptible in AD. So far, we
have found significant differences in the functional properties
of iPSC-derived astrocytes using whole-cell patch clamp
electrophysiology and calcium imaging, with phenotypic
variance amongst the different genotypes (homozygous E3
and E4). Our data revealed a significant decrease of 60%
in the sustained component of potassium channel current.
This in itself could have significant impact on the ability of
astrocytes to efficiently balance ion homeostasis specific
to APOE genotype. APOEs role in clearance of amyloid β
(Aβ) in AD is due in part to the physiology of astrocytes,
which internalize and degrade Aβ. The altered physiology
in our current model could potentially provide a better
understanding of APOE genotype in health and disease.
Speaker Biography
Talitha Kerrigan is a senior Research associate, Faculty of University of Bristol, UK and
She has completed PhD from university of Leeds, UK
e:
Talitha Kerrigan, Neurosurg 2017, 2:2
DOI: 10.21767/2471-9633-C1-005