Nanosymposia Presentations

1334 Pages·2014·5.72 MB·English

by  Michele Appley

When citing an abstract from the 2014 annual meeting please use the format below.

[Authors]. [Abstract Title]. Program No. XXX.XX. 2014 Neuroscience Meeting Planner.
Washington, DC: Society for Neuroscience, 2014. Online.

2014 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any
abstract or part of any abstract in any form must be obtained in writing by SfN office prior to
publication.
Nanosymposium
010. Neurogenesis and Neurotransmission in Neurodegenerative Diseases
Location: 152A
Time: Saturday, November 15, 2014, 1:00 PM - 2:45 PM
Presentation Number: 10.01
Topic: C.02. Alzheimer's Disease and Other Dementias
Support: R01 EB008432
R01 NS080655
R01 MH097268
R01 MH085667
P41 EB015922
Title: Capturing brain connectivity in Alzheimer’s disease by evolving the human connectome
Authors: *G. PRASAD1, S. H. JOSHI2, P. M. THOMPSON1;
1Dept. of Neurology, UCLA Sch. of Med., Imaging Genet. Ctr., Marina Del Rey, CA; 2Dept. of
Neurol., UCLA, Los Angeles, CA
Abstract: Diffusion MRI allows us to represents white matter connectivity as a set of fibers or
curves using tractography methods. These fibers are used to quantify the connectivity strength
between pairs of anatomical regions from a well known atlas of the cortex to create a
connectivity network of the living human brain. In diseases such as Alzheimer’s disease (AD),
this network configuration can become compromised and we can study the affected connections
to gain more insight into the disease. However, the regions from an anatomical atlas may not be
optimal for studying disease and we use a method call evolving partitions to improve
connectomics (EPIC) to pick the optimal regions to map connectivity in AD. We analyzed 87
participants the Alzheimer’s disease Neuroimaging Initiative (ADNI) dataset composed of 37
AD participants and 50 healthy older controls. The participants were scanned using structural
and diffusion MRI on a 3-Tesla GE Medical Systems. We computed fiber connectivity in each
participant using a global tractography algorithm and a set of cortical regions using the Desikan-
Killiany atlas in Freesurfer. The combination of these two results created connectivity networks
representing healthy controls and AD. We then used EPIC to evolve the cortical regions such
that the differences between controls and AD were maximized as assessed by the accuracy of a
machine learning classifier between the two groups (Fig. 1). We treated the standard anatomical
parcellation from Freesurfer as our baseline model and its corresponding accuracy as our
benchmark. The cross-validation accuracy using the anatomical parcellation was 82.7% (78.3%
specificity, 86% sensitivity). EPIC was able to improve on this accuracy by evolving the
parcellation to obtain an accuracy of 85.0% (81.0% specificity, 88% sensitivity). Our results
show that we are indeed able to find a better representation of brain connectivity for AD. This
new atlas of brain connectivity emphasizes the changes that occur with the onset of dementia and
could be a useful alternative to standard connectivity when studying the disease.

Disclosures: G. Prasad: None. S.H. Joshi: None. P.M. Thompson: None.

Nanosymposium
010. Neurogenesis and Neurotransmission in Neurodegenerative Diseases
Location: 152A
Time: Saturday, November 15, 2014, 1:00 PM - 2:45 PM
Presentation Number: 10.02
Topic: C.02. Alzheimer's Disease and Other Dementias
Support: Douglas and Ellen Rosenberg Foundation
Joseph Drown Foundation
NIH AG034427
Bredesen Acceleration Project, Sponsored Research Holdings, LLC
Title: The alpha7nAChR partial agonist, 5-HT3 antagonist, and APP-binding re-purposed
compound tropisetron increases sAPPalpha, lowers Abeta and p-tau, and normalizes cognition in
a murine Alzheimer's model
Authors: *P. SPILMAN1, O. DESCAMPS1, O. GOROSTIZA1, K. POKSAY1, J.
CAMPAGNA1, A. MATALIS1, C. PETERS-LIBEU1, R. RAO1, V. JOHN1,2, D. E.
BREDESEN1,2;
1Buck Inst. For Age Res., Novato, CA; 2Univ. of California, Los Angeles, CA
Abstract: It is thought the number of cases of Alzheimer's disease (AD) will rapidly increase in
the coming decades. AD is characterized by amyloid-beta (Abeta) plaques and tau neurofibrillary
tangles. As by the time of diagnosis substantial pathology is present, it is likely that anti-AD
therapy will require chronic, pre-symptomatic treatment; this will make drug safety imperative.
In AD there is a shift in amyloid precursor protein (APP) processing toward the anti-trophic
state, reducing sAPPalpha relative to sAPPbeta and Abeta species. Restoration of this balance
may be essential to reverse the underlying mechanisms that lead to AD. High-throughput
screening (HTS) of a clinical compound library in 7W CHO cells expressing huAPPwt was used
to identify “hits” increasing sAPPalpha. The hit tropisetron was re-tested in primary neuronal
culture, and then determined to be brain-permeable in pharmacokinetic analysis. A series of in
vivo studies were performed using 5-6 mo J20 PDAPP Swe/Ind and NTg mice, including a 28-
day study (0.5 mg/kg/day) wherein working memory was assessed using the Novel Object
Recognition (NOR) task, a 56-day study (0.5 mg/Kg/day) wherein spatial memory was tested by
Morris Water Maze (MWM) and 3-month study using 12-20 mo post-plaque J20 and NTg mice
treated orally at 4 mg/kg/day; NOR and spatial memory in the Novel Location Recognition
(NLR) paradigm were assessed pre-, mid- and end-study. Biochemical analysis included
sAPPalpha, sAPPbeta, and phospho-tau (AlphaLISA, Perkin-Elmer) and Abeta 1-40 and 1-42
(ELISA, Life Technologies) of combined hippocampal and entorhinal cortical tissue. IHC
analysis included plaque and synaptic load. Tropisetron increased sAPPalpha by 30% in HTS
and by 25% in primary culture. In the 28-day study, NOR was increased in tropisetron-treated
J20s to NTg levels at 14 days and was even higher than NTg controls at 28 days. sAPPalpha was
significantly increased and Abeta 1-40 and 1-42 significantly decreased. In the 56-day study,
tropisetron-treated mice showed improvements in MWM. sAPPalpha significantly increased and
Abeta 1-42 significantly decreased. Finally, tropisetron improved working and spatial memory at
both mid- and end-study in old J20 and NTg mice, and dramatically increased sAPPalpha and
decreased phospho-tau. Our iterative hierarchical screening method identified tropisetron which
was found to be effective at the human-equivalent doses, improving memory and the biomarkers
sAPPalpha, Abeta, and p-tau in brain tissue. As tropisetron has an excellent safety profile - and
as a result of the findings here - it is currently in clinical trials for the treatment of mild cognitive
impairment (MCI) and early AD.
Disclosures: P. Spilman: None. O. Descamps: None. O. Gorostiza: None. K. Poksay:
None. J. Campagna: None. A. Matalis: None. C. Peters-Libeu: None. R. Rao: None. V.
John: None. D.E. Bredesen: None.

Nanosymposium
010. Neurogenesis and Neurotransmission in Neurodegenerative Diseases
Location: 152A
Time: Saturday, November 15, 2014, 1:00 PM - 2:45 PM
Presentation Number: 10.03
Topic: C.02. Alzheimer's Disease and Other Dementias
Support: German Science Foundation (DFG) Grant PE1193/2-1
DZNE
Title: Purinergic signaling mediates astrocytic hyperactivity in vivo in a mouse model of
Alzheimer’s disease
Authors: A. DELEKATE1, M. FUECHTEMEIER2, M. BRUECKNER3, T. SCHUMACHER1,
A. HALLE3, *G. C. PETZOLD1;
1German Ctr. For Neurodegenerative Dis. (DZNE), Bonn, Germany; 2Exptl. Neurol., Charité,
Berlin, Germany; 3Ctr. for Advanced European Studies and Res. (Caesar), Bonn, Germany
Abstract: Astrocytes form dynamic networks in the brain, contribute to cerebrovascular
regulation, and support synaptic function. In Alzheimer's disease (AD), astrocytes adopt a
"reactive" phenotype, and have been shown to display hyperactivity. The goal of this study was
to identify the molecular signaling pathways governing astroglial hyperactivity, and to explore
the relationship between astrocytic network dysfunction and reactive astrocytosis as well as
cerebrovascular pathology. To this end, we used a standard mouse model of AD (APPPS1 line)
to investigate cellular calcium dynamics, cerebral blood flow and Aβ plaque topography in vivo
by multiphoton microscopy. We found that significantly more astrocytes were spontaneously
hyperactive in APPPS1 mice compared to wildtype age-matched littermates. This hyperactive
astroglial phenotype was most pronounced around Aβ plaques, and co-localized with reactive
astrogliosis. Moreover, APPPS1 mice displayed astrocytic intercellular wave-like events that
propagated across the cortex and in some cases were associated with cerebrovascular changes.
Astrocytic hyperactivity remained unchanged when we blocked synaptic transmission or
mGluR5-mediated neuron-to-astrocyte signaling. However, inhibition of P2 purinoreceptors
strongly reduced hyperactivity. Similarly, inhibition of nucleotide release through connexin
hemichannels also decreased hyperactivity. Inhibition of P2X receptors had no effect, while
blockade of IP3 receptor activation downstream of P2Y receptor activation reduced hyperactivity
and calcium waves. To better define the involved P2Y receptor subtype, we applied an
ectonucleotidase with high ATPase/ADPase ratio, thereby increasing tissue ADP concentration,
and found that this treatment strongly amplified hyperactivity and calcium waves, indicating an
involvement of ADP-sensitive P2Y receptors. In contrast, all of these interventions, except for
IP3R blockade, had no effect on astrocytic transients in wildtype littermates. In conclusion, we
have shown that astroglial network dysfunction is mediated by purinergic signaling in reactive
astrocytes, and that modulation of P2Y receptor activity or nucleotide release through
hemichannels may represent novel targets to ameliorate neuro-glial network dysfunction in AD.
Disclosures: A. Delekate: None. M. Fuechtemeier: None. M. Brueckner: None. A. Halle:
None. G.C. Petzold: None. T. Schumacher: None.

Nanosymposium
010. Neurogenesis and Neurotransmission in Neurodegenerative Diseases
Location: 152A
Time: Saturday, November 15, 2014, 1:00 PM - 2:45 PM
Presentation Number: 10.04
Topic: C.02. Alzheimer's Disease and Other Dementias
Support: R01AG033570
RC1 AG036208-01
Title: Depletion of neurogenesis induces cognitive deficits in Alzheimer’s disease
Authors: *C. L. HOLLANDS1, R. SCHLOESSER3, K. MARTINOWICH4, S. KERNIE5, O.
LAZAROV2;
2Anat. and Cell Biol., 1The Univ. of Illinois at Chicago, Chicago, IL; 3Univ. of Maryland Med.
Ctr., Baltimore, MD; 4The Johns Hopkins Univ. Sch. of Med., Baltimore, MD; 5Columbia Univ.,
New York, NY
Abstract: Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly. AD
is a learning and memory disorder, characterized by progressive loss of memory and cognitive
decline. About 95% of AD cases are sporadic, and aging is the greatest risk factor for the disease.
The molecular mechanism underlying memory loss is not fully understood. Increasing evidence
suggests that impairments in hippocampal neurogenesis take place early in mouse models of
familial Alzheimer’s disease. Taken together with the observation that neurogenesis declines
with age, this may suggest that impairments in hippocampal neurogenesis play a role in cognitive
deficits in AD. To address this hypothesis, we utilized a transgenic approach to temporally
regulate depletion of neurogenesis by nestin-regulated expression of δ-HSV-TK in neural
progenitor cells in the brain of APPswe/PS1ΔE9 animals. Depletion of neurogenesis was
manifested by a 75.7% (p=.004) decrease in nestin expressing cells and a 72% (p=.03) decrease
in neuroblasts in the subgranular layer, of the hippocampus. This was matched by an 86%
decrease in new neurons in the granular layer as assessed by expression of NeuN and
incorporation of 5’-Bromo-2’deoxyuridine (BrdU). Significantly, we observed that the
combination of FAD-linked genes and loss of neurogenesis enhanced memory deficits at 4
months of age in the Radial Arm Water Maze test, Pattern Separation and Fear Conditioning
tests. These deficits were not observed when neurogenesis was ablated only or when
APPswe/PS1DE9 mice were used only. These experiments provide, for the first time, evidence
that impairments in neurogenesis promote cognitive deficits in Alzheimer’s disease.
Disclosures: C.L. Hollands: None. R. Schloesser: None. K. Martinowich: None. S. Kernie:
None. O. Lazarov: None.

Nanosymposium
010. Neurogenesis and Neurotransmission in Neurodegenerative Diseases
Location: 152A
Time: Saturday, November 15, 2014, 1:00 PM - 2:45 PM
Presentation Number: 10.05
Topic: C.02. Alzheimer's Disease and Other Dementias
Support: R01AG033570
RC1 AG036208-01
Title: Reduced levels of presenilin-1 in adult hippocampal neural progenitor cells induces
learning and memory deficits
Authors: *J. A. BONDS1, Y. KUTTNER-HIRSHLER2, N. BARTOLOTTI2, A. GADADHAR2,
M. PIZZI3, R. MARR3, O. LAZAROV2;
1Anat. and Cell Biol., Univ. of Illinois, Chicago, Chicago, IL; 2Univ. of Illinois at Chicago,
Chicago, IL; 3Rosalind Franklin Univ. of Med. and Sci., Chicago, IL
Abstract: Presenilin-1 (PS1) is the catalytic core of the aspartyl protease γ-secretase, which
cleaves numerous membrane proteins, including amyloid precursor protein, notch-1 and other
proteins involved in neurogenesis. Mutations in PS1 cause familial Alzheimer’s disease (FAD), a
progressive neurodegenerative disease characterized by loss of memory and cognitive decline.
We previously showed that PS1 regulates neural progenitor cell differentiation in the adult brain.
New neurons are thought to play a role in aspects of learning and memory. However, it is not
clear if PS1 plays a role in neurogenesis-dependent learning and memory. To determine that, we
injected lentivirus expressing small interfering RNA (siRNA) to knockdown PS1 expression in
neural progenitor cells in the dentate gyrus of adult mice and evaluated their learning and
memory performance 3 months and 6 months following the injection. Here we show that down-
regulation of PS1 in hippocampal neural progenitor cells causes progressive deficits in
hippocampus-dependent learning and memory function. Furthermore, we demonstrate a decrease
in dendritic arborization and spine density in neurons infected with the PS1 lentivirus. These
results support a role for neurogenesis in learning and memory and provide a mechanism by
which dysfunction of PS1 in Alzheimer’s disease compromises learning and memory.
Disclosures: J.A. Bonds: None. Y. Kuttner-Hirshler: None. N. Bartolotti: None. A.
Gadadhar: None. M. Pizzi: None. R. Marr: None. O. Lazarov: None.

Nanosymposium
010. Neurogenesis and Neurotransmission in Neurodegenerative Diseases
Location: 152A
Time: Saturday, November 15, 2014, 1:00 PM - 2:45 PM
Presentation Number: 10.06
Topic: C.02. Alzheimer's Disease and Other Dementias
Support: R01AG033570
1RC1AG036208-01
NS20498
Title: Cyclic-AMP Response Element Binding Protein (CREB) signaling is impaired in a mouse
model of Alzheimer’s disease
Authors: *N. BARTOLOTTI1, Y.-S. HU1, D. STORM2, O. LAZAROV1;
1Univ. of Illinois At Chicago, Chicago, IL; 2Univ. of Washington, Seattle, WA
Abstract: Alzheimer’s disease is a neurodegenerative disorder characterized by cognitive
impairment and memory deficits. The phosphorylation of cyclic-AMP Response Element
Binding Protein (CREB) is a critical step in the formation of memories. Phosphorylation of
CREB on Serine 133 (pCREB-SER133) is necessary for Cyclic-AMP Response Element (CRE)-
driven transcription of genes important for learning and memory such as Brain-Derived
Neurotrophic Factor (BDNF). Here, we show that steady state levels of pCREB in the
APPSwe/PS1E9 mouse model of Alzheimer’s disease are reduced compared to levels in the
brains of wild type littermates. Notably, following experience in an enriched environment, an
experience that increases synaptic plasticity and hippocampal neurogenesis, phosphorylated
CREB is increased in the hippocampus of wild-type mice, but not in the hippocampus of
APPSwe/PS1e9 mice. Reporter CRE-β-galactosidase/ APPSwe/PS1E9 mice exhibit reduced
CRE-gene transcription in the hippocampus compared to CRE-β-galactosidase/wild type
littermates. These impairments in CREB signaling are observed prior to the onset of amyloid
pathology and inflammation in these mice. Taken together, these experiments suggest that a
critical pathway in learning and memory is impaired in FAD-linked APPSwe/PS1E9 mice and
may underlie learning and memory impairments exhibited by these mice.
Disclosures: N. Bartolotti: None. Y. Hu: None. D. Storm: None. O. Lazarov: None.

Nanosymposium
010. Neurogenesis and Neurotransmission in Neurodegenerative Diseases
Location: 152A
Time: Saturday, November 15, 2014, 1:00 PM - 2:45 PM
Presentation Number: 10.07
Topic: C.02. Alzheimer's Disease and Other Dementias
Support: Zenith Award ZEN-12-241433 from Alzheimer’s Association, USA)
Title: Rescue of cognitive deficit with a neurogenic/neurotrophic compound in 3xTg-AD mouse
model
Authors: *N. BAAZAOUI1,2, K. IQBAL1;
1New York Inst. For Basic Res., Staten Island, NY; 2Biol., CUNY the graduate center, New
York, NY
Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disease and the sixth
leading cause of death in the United States. Till now there is no effective drug that can stop or
slow the progression of the disease. The most popular approach to treat AD is to inhibit
neurodegeneration. However, another exciting strategy is to treat AD by shifting the balance
from neurodegeneration to regeneration of the brain. Here we report the therapeutic beneficial
effect of a neurogenic/neurotrophic compound called P021 (Li, B et al. FEBS letters, 2008) on
cognitive performance in 3xTg-AD mouse model of AD. At three months of age 3xTg-AD mice
were tested for reference memory by Morris Water Maze task and right after they were put on
P021 diet. At the age of 12 months these mice were tested again by Morris Water Maze task
employing 3 probe trials: the first probe trial was given 24 h after the last training session, the
second probe trial 20 days after the first probe trial and the third probe trial 20 days later. At 18
months of age the mice were tested by novel object location test to evaluate short-term spatial
reference memory. Then at 20 months of age they were tested for episodic memory by novel
object recognition test. The 3 month 3xtg-AD mice showed a clear impairment in reference
memory. At 12 months of age the 3xTg-AD mice were found impaired by the Morris Water
Maze task during acquisition seen as longer escape latency and less time spent in target quadrant
compared to wild type (WT) animals in all the probe trials. The memory impairment was rescued
in the P021-treated 3xTg-AD mice. At 18 months of age in the object location test, the 3xTg-AD
mice spent more time investigating the familiar location of the object than the novel one, and the
treatment with P021 recued this impairment. Using the novel object recognition task at 20
months of age we found that the 3xTg-AD mice spent more time investigating the familiar object
than the novel one, and this impairment was rescued in P021 treated animals. All together these
data show that chronic treatment with neurogenic/neurotrophic compound can rescue the
cognitive impairment in the 3xtg-AD mice.
Disclosures: N. Baazaoui: None. K. Iqbal: None.

Nanosymposium
012. Demyelinating Disorders
Location: 152B
Time: Saturday, November 15, 2014, 1:00 PM - 4:15 PM
Presentation Number: 12.01
Topic: C.09. Demyelinating Disorders
Support: NMSS RG4078
Title: Neurodegenerative consequences of episodic metabolic stress in oligodendrocytes
Authors: *D. Z. RADECKI1, A. GOW2;
2CMMG, 1Wayne State Univ., Detroit, MI