1/9/19 1 Sandrine Thuret, PhD Generation of New Hippocampal Neurons in the Adult Brain: Implication for Mental Health INSTITUTE OF PSYCHIATRY, PSYCHOLOGY & NEUROSCIENCE Basic and Clinical Neuroscience Department of Basic and Clinical Neuroscience, Cells and Behaviour Unit Institute of Psychiatry, Psychology and Neuroscience, King’s College London. WEBSITE https://tinyurl.com/Thuret-Lab TWITTER @thudrine Disclosure Statement of Financial Interest I, (Sandrine Thuret), DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. INSTITUTE OF PSYCHIATRY, PSYCHOLOGY & NEUROSCIENCE Basic and Clinical Neuroscience Department of Basic and Clinical Neuroscience, Cells and Behaviour Unit Institute of Psychiatry, Psychology and Neuroscience, King’s College London. WEBSITE https://tinyurl.com/Thuret-Lab TWITTER @thudrine ADULT HIPPOCAMPAL NEUROGENESIS Regulatory Mechanisms Molecular Environmental Health Disease Prevention Intervention Prediction Monitoring
16
Embed
INSTITUTE OF PSYCHIATRY, PSYCHOLOGY & NEUROSCIENCE · Department of Basic and Clinical Neuroscience, Cells and Behaviour Unit Institute of Psychiatry, Psychology and Neuroscience,
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
1/9/19
1
Sandrine Thuret, PhD
Generation of New Hippocampal Neurons in the
Adult Brain: Implication for Mental Health
INSTITUTE OF PSYCHIATRY, PSYCHOLOGY & NEUROSCIENCE
B a s i c a n d C l i n i c a lN e u r o s c i e n c e
Department of Basic and Clinical Neuroscience, Cells and Behaviour UnitInstitute of Psychiatry, Psychology and Neuroscience, King’s College London.WEBSITE https://tinyurl.com/Thuret-Lab
TWITTER @thudrine
Disclosure Statement of Financial Interest
I, (Sandrine Thuret),
DO NOT have a financial interest/arrangement or affiliation with one or
more organizations that could be perceived as a real or apparent
conflict of interest in the context of the subject of this presentation.
INSTITUTE OF PSYCHIATRY, PSYCHOLOGY & NEUROSCIENCE
B a s i c a n d C l i n i c a lN e u r o s c i e n c e
Department of Basic and Clinical Neuroscience, Cells and Behaviour UnitInstitute of Psychiatry, Psychology and Neuroscience, King’s College London.WEBSITE https://tinyurl.com/Thuret-LabTWITTER @thudrine
ADULT HIPPOCAMPAL
NEUROGENESIS
Reg
ulat
ory
Mec
hani
sms
Molecular
Environmental
Health
Disease
Prev
entio
nIn
terv
entio
n
Prediction
Mon
itorin
g
1/9/19
2
“Once development was ended, the fonts of growth and regeneration of the axons anddendrites dried up irrevocably. In the adult centers, the nerve paths are something fixed, andimmutable: everything may die, nothing may be regenerated.”
Santiago Ramon y Cajal, 1928
Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats.
Altman & Das, 1965
Adult Neurogenesis?
Adult hippocampal neurogenesis
N euN C A G G FP G FA P
Adult hippocampal neurogenesis in humans
1/9/19
3
Adult hippocampal neurogenesis in humans
Functional Relevance of Adult Hippocampal Neurogenesis: Learning and Memory
New Dentate Gyrus granule cells:• Increase spatial memory capacity
• Reduce interference between memories (pattern separation)
• Add information about time to memories
• Are involved in forgetting of established context-memories.
•Adult Hippocampal Neurogenesis is reduced in some animalmodels of depression.
•Many treatments for depression promote Adult HippocampalNeurogenesis and/or are dependent on functional neurogenesis.
Functional Relevance of Adult Hippocampal Neurogenesis: Mood
1/9/19
4
Adult Hippocampal Neurogenesis: Regulated by environmental influences
Adult Hippocampal Neurogenesis: is modifiable
controls
runners
Adult Hippocampal Neurogenesis emerging as Target of choice?
1/9/19
5
Our hippocampal neurogenesis Lines of Research
Dem
elza
Smee
th
Amin
aM
cDia
rmid
Hyun
-ah
Lee
Chia
ra d
e Lu
cia
Curie
Kim
Thom
as
Berg
er
Andr
ea
Du P
reez
Edin
aSi
lajd
zic
Alish
Palm
os
Animal Models
=
=
=
A d L ib i t u m ( A L )
In t e r m it t e n t F a s t in g ( IF )
C a lo r ie R e s t r ic t e d ( C R )
1 0 0 %
9 0 %
9 0 %
DH VHDCX
Wt
kl/k
l
Intermittent fasting enhances recognitionmemory and adult hippocampal neurogenesisvia the longevity gene Klotho and miR-497.
Dias et al. in preparation
Understanding the molecularneurobiology of depression.
Musaelyan et al. 2018 and in preparation
CON UCMSNeurogenesis depletion using anti-mitotic drug Temozolomide causeschanges in affective behaviour inmice.
Egeland et al. Translational Psychiatry2017
Human Hippocampal Stem Cell line – Controlled Environment
+EGF+FGF
Differentiation
CellProliferationAdd
4-OHT
Remove4-OHTEGFFGF
Identification and validation of new genes and microRNAs involved
in Proliferation and/or Neuronal Differentiation
1/9/19
6
Human Hippocampal Stem Cell line – Stress Model
Identification of drugs for
repositioning as new
antidepressants
Powel et al. 2017a, b
Identification of the mode of action of antidepressants
Anacker et al., 2011, 2013a, 2013b
Identification of nutrient-derived
bioactivespreventing stress-induced decrease of neurogenesis
Stangl et al. in preparation
AHN: A Target for intervention
HEALTHDISEASE
PREVENTION
TREATMENT
AHN: A Biomarker for Health status, disease prediction and monitoring
HEALTHDISEASE
PREDICTION
MONITORING
AHN: A Biomarker for Health status, disease prediction and monitoring
Data: Tytus Murphy and Chiara de LuciaImage from Lopez-Otin et al., 2013
NAMPT SOD2
DIABLO
POLGDNML1
Mitochondrialactivity
H2A.XPARP1 XRCC2
TERT
SIRT1 pSIRT1AKT
pAKT
SIRT1 pSIRT1
AMPK pAMPK
NfKBpNfKB
UCHL1
ATF4
ATG5S6 pS6
CDKN2A
CDKN2B
CDKN2D
CDKN1A
TP53
TNFR1FADD
Older donor serum induces a molecular ageing phenotype in hippocampal stem cells
1/9/19
10
Old_Young in vitro parabiosis recapitulates some molecular hallmarks of AgeingAgeing expression profile of hippocampal stem cells exposed to Old v. Young serum
Y (Mean age: 29.7); O (Mean age: 77.7)
Ageing Cellular profile of hippocampal stem cells exposed to Old v. Young serum
Age is associated with increased heterogeneity:Reflecting a lifetime of unequal exposure to changing environments / different life styles e.g. diet à Chronological age ⍀ biological age
The systemic environment is a major determinant of hippocampal stem cell biology during ageing.
Mu & Gage, 2011Maruszak et al. 2013
Systematic comparison needed withsame:
-Age-gender-genetic background-neuropathology stage-methods of neurogenesis detection
Hippocampal neurogenesis in Alzheimer’s Disease (rodent models)
Gatt et al. 2018
Hippocampal neurogenesis in Alzheimer’s Disease (human postmortem tissues)
1/9/19
11
Hippocampal neurogenesis in Alzheimer’s Disease
Alterations in AHN occur at the very early stage of AD progression
Prior to processes that may secondarily affect neurogenesis (neuronal loss, amyloiddeposition and inflammation).
AHN= An integral part of AD pathology
-Can we clarify the longitudinal changes in hippocampal neurogenesis during AD progression?
-Can we predict AD conversion from Mild Cognitive Impairment (MCI)?
Hippocampal neurogenesis in Alzheimer’s Disease
MCI AD
L o n g i t u d i n a l p a t i e n t s s e r u m s a m p l e s
Longitudinal serum samples AddNeuroMed and KHP-DCR cohorts
conversion
M ild cognitive impairment
Dementia due to Alzheimer’s disease
Longitudinal blood collection from MCI converters to AD(N=38, 2-6 follow-up visits)
M ild cognitive impairment (non-converters)
Longitudinal blood collection from MCI non-converters (N=18, 3-6 follow-up
visits)
Aleksandra Maruszak et al., bioRxiv 175604; doi: https://doi.org/10.1101/175604
1/9/19
12
Can we monitor AD progression?
Signatures of disease progression
DA
PI
CC
3K
i67
MCI Alzheimer’s disease
p=0.023
p=0.002
p<0.0001
Increased cell count
Increased apoptotic cell death
Decreased proliferation
Signatures of conversion to AD (proliferation assay)
Mixed effects regression models for repeated measuresP-values represent significance of the fitted model.
Aleksandra Maruszak et al., bioRxiv 175604; doi: https://doi.org/10.1101/175604
Increased number of neuroblasts
MCI Alzheimer’s disease
DAP
ID
cxM
ap2
p=0.021
p=0.044
p=0.037
Increased cell count
Increased number of neurons
Signatures of conversion to AD (differentiation assay)
Mixed effects regression models for repeated measuresP-values represent significance of the fitted model.
Aleksandra Maruszak et al., bioRxiv 175604; doi: https://doi.org/10.1101/175604
1/9/19
13
Can we distinguish MCI converters from MCI non-converters?
Signatures of disease progression
MCI converters and non-converters have a different cellular profile
AVERAGE CELL COUNT (differentiation)
p<0.0001 p<0.0001
p=0.0001, R2= 0.099, AdjR2= 0.093
AVERAGE CELL COUNT (proliferation)
PROLIFERATION (%Ki67) APOPTOTIC CELL DEATH (%CC3, proliferation)
p=0.0001p=0.0005
NEUROGENESIS (%Map2)
p<0.0001, R2= 0.2631, AdjR2= 0.258
APOPTOTIC CELL DEATH (%CC3, differentiation)
Mixed effects regression models for repeated measuresP-values represent significance of the fitted model.
Aleksandra Maruszak et al., bioRxiv 175604; doi: https://doi.org/10.1101/175604
Who will convert to AD?
Signatures of disease progression
1/9/19
14
Who will convert to AD?
•Baseline serum sample data•Stepwise logistic regressionèModel predicting conversion from MCI to AD with an accuracy of 96.75%
96.75% chance of correct classification
Area under the Receiver Operating Characteristic (ROC)
Aleksandra Maruszak et al., bioRxiv 175604; doi: https://doi.org/10.1101/175604
1/9/19
15
1- Can we monitor AD progression? ✓Conversion to AD is significantly associated with changes in hippocampalprogenitor cell count, proliferation, cell death and neurogenesis.
Our human hippocampal progenitor cell-based assay enables monitoring disease progression and predicting conversion to AD
3- Can we predict AD conversion? ✓Education and baseline assay readouts on hippocampal progenitor cellcount, proliferation and cell death predict conversion to AD with highaccuracy.
2- Can we distinguish MCI converters from MCI non-converters? ✓MCI converters can be distinguished from MCI non-converters usingmarkers of proliferation, neurogenesis and cell death.
Can we modify the probability to convert from MCI to AD?
m cp (marg insconplo t) a fter S TA TA fitting log is tic regress ion m odels.A verage adjusted pred ic tion for each of the observed va lues for education or C C 3, w hile other variab les are le ft a t the ir observed va lues.
§Validation study has started.
§Up to 3.5 years for intervention to delay AD conversion/ for stratification inclinical trials.
§Assay for testing candidate molecules to rescue the conversion cellularphenotype.
§Assay for monitoring interventions/disease progression.
Our human hippocampal progenitor cell-based assay enables monitoring disease progression and predicting conversion to AD
1/9/19
16
AcknowledgementsThomas BergerCurie KimChiara De LuciaAndrea Du PreezDemelza SmeethAmina McDiarmidHyun-ah LeeEdina SilajdzicAlish Palmos