neurogenesis in the adult brain, gene networks, and alzheimer's disease

214 Pages·2017·2.58 MB·English

by  Horgusluoglu, Emrin

NEUROGENESIS IN THE ADULT BRAIN, GENE NETWORKS, AND
ALZHEIMER’S DISEASE

Emrin Horgusluoglu

Submitted to the faculty of the University Graduate School
in partial fulfillment of the requirements
for the degree
Doctor of Philosophy
in the Department of Medical and Molecular Genetics,
Indiana University

August 2017
Accepted by the Graduate Faculty of Indiana University, in partial
fulfillment of the requirements for the Degree of Doctor of Philosophy.

Andrew J. Saykin, PsyD, Chair

Doctoral Committee
Tatiana Foroud, PhD

Yunlong Liu, PhD
May 15, 2017

Kwangsik Nho, PhD

Li Shen, PhD

ii
ACKNOWLEDGEMENT

Firstly, I would like to express my sincere gratitude to my mentor Dr. Saykin and
my co-mentor Dr. Nho for the continuous support of my PhD study and related
research, for their patience, motivation, and immense knowledge. Their guidance
helped me in all the time of research and writing of my dissertation.

Besides my advisor, I would like to thank the rest of my thesis committee: Dr.
Foroud, Dr. Liu and Dr. Shen for their insightful comments and encouragement,
but also for the hard question which incented me to widen my research from
various perspectives. I thank my fellow lab-mates and friends for the stimulating
discussions, and working together.

My sincere thanks also goes to Dr. Malacinski who provided me an opportunity to
come to Indiana University, School of Medicine and supported me more than ten
years in my scientific career.

I also would like to thank my son, Efe K. Guner, for understanding my long work
hours and schedule. We shared great laughs and memories during my PhD
training. We planned our success and life together. Thank you for supporting me
and motivating me.

iii
Last but not the least, I also would like to thank my mother, Nehrin Gurel and my
sister, Elif Tokel for always supporting me and encouraging me with their help
and best wishes. I would like to thank to my husband and family for supporting
me and believing me throughout writing this thesis and my life in general.
iv
Emrin Horgusluoglu

NEUROGENESIS IN THE ADULT BRAIN, GENE NETWORKS, AND
ALZHEIMER’S DISEASE

New neurons are generated throughout adulthood in two regions of the brain, the
dentate gyrus of the hippocampus, which is important for memory formation and
cognitive functions, and the sub-ventricular zone of the olfactory bulb, which is
important for the sense of smell, and are incorporated into hippocampal network
circuitry. Disruption of this process has been postulated to contribute to
neurodegenerative disorders including Alzheimer’s disease [1]. AD is the most
common form of adult-onset dementia and the number of patients with AD
escalates dramatically each year. The generation of new neurons in the dentate
gyrus declines with age and in AD. Many of the molecular players in AD are also
modulators of adult neurogenesis, but the genetic mechanisms influencing adult
neurogenesis in AD are unclear. The overall goal of this project is to identify
candidate genes and pathways that play a role in neurogenesis in the adult brain
and to test the hypotheses that 1) hippocampal neurogenesis-related genes and
pathways are significantly perturbed in AD and 2) neurogenesis-related pathways
are significantly associated with hippocampal volume and other AD-related
biomarker endophenotypes including brain deposition of amyloid-β and tau
pathology. First, potential modulators of adult neurogenesis and their roles in
neurodegenerative diseases were evaluated. Candidate genes that control the
v
turnover process of neural stem cells/precursors to new functional neurons
during adult neurogenesis were manually curated using a pathway-based
systems biology approach. Second, a targeted neurogenesis pathway-based
gene analysis was performed resulting in the identification of ADORA2A as
associated with hippocampal volume and memory performance in mild cognitive
impairment and AD. Third, a genome-wide gene-set enrichment analysis was
conducted to discover associations between hippocampal volume and AD-
related endophenotypes and neurogenesis-related pathways. Within the
discovered neurogenesis enriched pathways, a gene-based association analysis
identified TESC and ACVR1 as significantly associated with hippocampal volume
and APOE and PVLR2 as significantly associated with tau and amyloid beta
levels in cerebrospinal fluid. This project identifies new genetic contributions to
hippocampal neurogenesis with translational implications for novel therapeutic
targets related to learning and memory and neuroprotection in AD.

Andrew J. Saykin, PsyD, Chair

vi
TABLE OF CONTENTS

List of Tables …………………………………………………………………………....ix
List of Figures…………………………………………………………………………..xii
List of Abbreviations…………………………………………………………………..xiv
I. Adult neurogenesis and neurodegenerative diseases: A systems biology
perspective
A. Introduction………………………………………………………………………1
i. Neurogenesis Role in Cognition……………………………………….3
ii. Cell Types in Adult Neurogenesis……………………………………..5
iii. Neurogenesis Role in Hippocampus………………………………...10
B. Modulators of Adult Neurogenesis…………………………………………..11
i. Signaling Transduction in Adult Neurogenesis……………………..13
ii. Vascular System and Angiogenesis…………………………………18
iii. Metabolic Factors and Their Role in Adult Neurogenesis…………20
iv. Immune System and Neurogenesis…………………………………23
v. Epigenetic Modulators………………………………………………...28
C. Role of Genetic Variation in Adult Neurogenesis…………………………..30
D. Adult Neurogenesis and Neurodegenerative Diseases……………………32
E. Therapeutic Research Focused on Adult Neurogenesis………………….41
F. Discussion………………………………………………………………………44
vii
II. Targeted neurogenesis pathway-based gene analysis identifies ADORA2A
associated with hippocampal volume in mild cognitive impairment and
Alzheimer’s disease
A. Introduction……………………………………………………………………..46
B. Materials and Methods………………………………………………………..52
C. Results………………………………………………………………………….63
D. Discussion………………………………………………………………………81
III. Genome-wide association analysis of hippocampal volume identifies
enrichment of neurogenesis-related pathways
A. Introduction…………………………………………………………………86
B. Materials and Methods……………………………………………………88
C. Results………………………………………………………………………95
D. Discussion………………………………………………………………...105
IV. Genome-wide association analysis of AD pathology-related phenotypes
identifies enrichment of neurogenesis-related pathways
A. Introduction………………………………………………………………..109
B. Materials and Methods…………………………………………………..111
C. Results…………………………………………………………………….117
D. Discussion………………………………………………………………...127
V. Conclusion and Future Directions……………………………………………….130
References……………………………………………………………………………137
Curriculum Vitae

viii
LIST OF TABLES

1. Demographic and clinical characteristics of ADNI participants…………………...53

2. 81 genes of gene-based association results in the discovery sample for
hippocampal volume using common variants (MAF ≥ 0.05) where empirical
p-values were calculated using 20,000 permutations in PLINK…………………..64

3. Association of rs9608282 in ADORA2A with neuroimaging phenotypes and
memory composite scores with and without diagnosis (DX)
adjustment……………………………………………………………………..............67

4. Meta-analysis of ADORA2A with hippocampal volume in three independent
cohorts: ADNI, AddNeuroMed and IMAS…………………………………………...69

5. Meta-analysis of rs9608282 with hippocampal volume in three independent
cohorts: ADNI, AddNeuroMed and IMAS…………………………………..............69

6. Demographic and clinical characteristics of ADNI participants………….............90

7. Molecular Signatures Database (MSigDB) GO Ontology pathways enriched

for hippocampal volume…………………………………………………………........98

ix
8. Molecular Signatures Database (MSigDB) GO Ontology pathways enriched
with 2 years hippocampal atrophy………………………………............................99

9. Gene-based association results (p-value) of four significant genes for
hippocampal volume using common variants (MAF ≥ 0.05), where p-values
were calculated using GATES software…………………………………………...100

10. Gene-based association results (p-values) of four genes for composite
memory scores using common variants (MAF ≥ 0.05), where empirical p-values
were calculated using 20,000 permutations in PLINK……………………………101

11. SNP-based analysis results for memory scores in ADNI……………………….102

12. GSEA pathway analysis result showed that six pathways are related to
neurogenesis after Bonferroni correction………………………………………….104

13. Molecular Signatures Database (MSigDB) GO Ontology pathways enriched

for CSF total tau and p-tau levels and tau PET…………………………………...119

14. Gene-based association analysis of genes linked to the enriched
neurogenesis-related pathways…………………………………………………….121

x