Please use this identifier to cite or link to this item:
Neuroprotective Potential of the N-Terminal Beta Amyloid Peptide Fragment in the Neurodegeneration, Synaptic Dysfunction and Memory Deficits in Models of Alzheimer’s Disease.
|Title:||Neuroprotective Potential of the N-Terminal Beta Amyloid Peptide Fragment in the Neurodegeneration, Synaptic Dysfunction and Memory Deficits in Models of Alzheimer’s Disease.|
|Authors:||Alfulaij, Naghum E. R. I.|
|Contributors:||Cell & Molecular Biology (department)|
|Date Issued:||Dec 2017|
|Publisher:||University of Hawaiʻi at Mānoa|
|Abstract:||Beta amyloid (Aβ) plays a central role in the pathogenesis of Alzheimer’s disease|
(AD). It is produced by the sequential cleavage of amyloid precursor protein (APP) by
β- and γ-secretases. This amyloidogenic pathway produces peptides 38-42 amino
acids in length, based on the sites cleaved by γ-secretase. Aβ1-42 is the predominant
peptide species found in neuritic plaques. Its accumulation and impaired clearance are
associated with disease progression. An alternative pathway has been proposed
wherein short, N-terminal Aβ fragments are produced. The N-terminal fragments are
hydrophilic, making them soluble and less likely to aggregate into plaques. Aβ1-15 is the
N-terminal Aβ fragment of focus in this study. It is produced by the sequential cleavage
of APP by β- and α-secretases followed by a carboxypeptidase. Aβ1-15 is also
upregulated in AD patients suggesting a possible compensatory switch between
pathways to suppress Aβ1-42 production. We have recently shown that Aβ1-15 can
enhance long-term potentiation (LTP) in wild-type hippocampal synapses at very low
(fΜ) concentrations. Aβ1-15 was also shown to reverse the LTP block incurred by Aβ1-42,
as well as rescue LTP deficits in APPswe mice. This fragment has a potent and
effective signaling activity via nicotinic acetylcholine receptors (nAChRs). Taken
together, these data support a neuromodulatory function and a possible neuroprotective
action for Aβ1-15. This study focuses on the effects of Aβ1-15 on Aβ1-42 toxicity in various
neuronal models, including in vitro NG108-15 hybrid neuroblastoma cells, ex vivo
hippocampal neuron cultures and in vivo wild-type and AD model-APP mice.
We explored Aβ1-15 neuroprotection against Aβ-mediated neurodegeneration in
vitro by incubating our differentiated neuroblastoma cell line with different treatment
combinations and across different time points in order to examine both the potency of
Aβ1-15 as well as the different ways by which Aβ1-15 might be affecting Aβ1-42 toxicity.
Specifically, we explored the possibilities of Aβ1-15 priming by pretreating cells with Aβ1-
15 before the addition of the toxic Aβ1-42, competition of the two fragments by
combination treatment, or rescue experiments by adding Aβ1-15 after addition of Aβ1-42 to
determine whether Aβ1-15 can reverse or halt toxicity caused by Aβ1-42. Cellular toxicity
was assessed as oxidative stress (production of reactive oxygen species, ROS) and
apoptotic cell death. Next, we investigated the neuroprotective effects of Aβ1-15 ex-vivo
by establishing primary hippocampal neuron cultures to confirm neuroprotection in a
more physiologically relevant neuronal model. We then explored the potential for the
Aβ1-15 to protect or reverse (rescue) synaptic dysfunction and memory deficits resulting
from Aβ synaptotoxicity. Changes in synaptic plasticity were assessed by measuring
LTP in acute mouse hippocampal slices. Furthermore, we inspected the potential for
rescue by Aβ1-15 of LTP in APPswe hippocampal slices known to have LTP deficits.
Lastly, we explored the effect of Aβ1-15 in different behavior paradigms on 5XFAD (FAD:
familial Alzeimer’s disease) mice, a model expressing APPswe, APP-London and APPFlorida
mutant transgenes as well as two mutant presenilin (PS1) transgenes, which
accumulates high levels of Aβ over an accelerated timeframe (months). The behaviors
examined were those related to deficits observed AD, namely contextual fear
conditioning, novel object recognition and elevated plus maze to examine effects on
memory processing, recognition memory and anxiety.
We were able to show that the Aβ1-15 protected against all measures of Aβ-
triggered neurotoxicity and neuronal dysfunction: oxidative stress, DNA fragmentation,
apoptotic cell death, synaptotoxicity and behavioral deficits. Notably, Aβ1-15 prevented
LTP inhibition caused by Aβ1-42 treatment and, when injected into the hippocampus was
able to rescue memory in contextual fear conditioning as well as decrease anxiety in the
5XFAD mice. To address preliminarily the possible molecular mechanisms underlying
the rescue by Aβ1-15 of memory deficits in the 5XFAD, we explored signaling pathways
known to be involved in Aβ synaptotoxicity. We observed a substantial upregulation of
the glutamate receptor GluR2 and phosphorylated CREB in mouse hippocampi injected
with the Aβ1-15, giving us insight into the specific actions of N-terminal fragment.
In summary, the data show that Aβ1-15 fully protected against Aβ1-42 –induced
cellular toxicity, synaptotoxicity and behavioral deficits. Taken together, the data support
our hypothesis that the N-terminal fragment (Aβ1-15) is not only neuroprotective against
acute Aβ1-42 toxicity, but also has the ability to rescue memory in 5XFAD mice,
potentially introducing a new avenue for AD therapeutics.
|Description:||Ph.D. Thesis. University of Hawaiʻi at Mānoa 2017.|
|Rights:||All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.|
|Appears in Collections:||
Ph.D. - Cell and Molecular Biology|
Please email email@example.com if you need this content in ADA-compliant format.
Items in ScholarSpace are protected by copyright, with all rights reserved, unless otherwise indicated.