Age-Associated Endocrine Dysfunction

Increases Risk of Neurodegenerative

Diseases

ISHWAR PARHAR

Brain Research Institute,

School of Medicine and Health Sciences

Monash University

MEIJI UNIVERSITY MAY19-25, 2019

Monash University Malaysia is jointly owned by Monash University and the Jeffrey Cheah Foundation

Sex Differences in Neurodegenerative

and Neuropsychiatric Diseases

2

Disease Women : Men (%)

Rett syndrome 100 : 0

Anorexia nervosa 93 : 7

Bulimia 75 : 25

Alzheimer’s Disease 74 : 26

Posttraumatic stress disorders 70 : 30

Anxiety disorder 67 : 33

Depression 63 : 37

Parkinson’s Disease 40 : 60

Amyotropic lateral sclerosis 33 : 67

Schizophrenia 27 : 73

ADHD 20 : 80

Autism 20 : 80

Kallmann’s syndrome 17 : 83

Kleine-Levin syndrome 0 : 100

Swaab et al. (2003) Neurobiology of Aging

Conception

Gestation

Infancy

Childhood Puberty Adult

Gonadal hormones Testosterone

Estrogen

THERAPEUTIC USE OF STEROIDS

Menopause

HRT low risk

10 years

HRT high risk

cancer

Senescence

GnRH

PITUITARY

GONADS

Hypothalamic Regulation of Reproduction

Gonadotropin-releasing hormone

EGFP-GnRH neurons

LH/FSH

Evolutionarily conserved Parhar et al (1993) Neurosci lett

Lim, Parhar et al (2013) Cell and Tissue Research

Fish

rat

human

Estrogen and testosterone

Monash University Malaysia is jointly owned by Monash University and the Jeffrey Cheah Foundation

GnRH

LH/FSH

Estrogen,

Testosterone

Activin, Inhibin

Brain(hypothalamus)

Pituitary

Reproduction

Gonads

HYPOTHALAMUS

cognition

GnRH-R in hippocampus

Prange-Kiel et al 2008 JBC

Laure Schang et al 2011 Endocrinology

Central reproductive peptide

GnRH-induced LH pulse

Young

Aged

•Attenuated LH surges in aged females

leading to acyclic estrous

Aged GnRH

neuronal characteristics

•Unaltered neuronal

numbers, morphology and

distribution

•Altered GnRH terminals

•Decreased GnRH pulsatile

release

•Decreased GnRH neuronal

activation

Neurodegenerative Disease

Monash University Malaysia is jointly owned by Monash University and the Jeffrey Cheah Foundation

7

The ageing process

Cognitive decline

Neurodegeneration

Neuropsychiatric disorders

The Reproductive Axis

GnRH

Pituitary

Gonads

Estrogen

Testosterone

Decline

Reproduction

Senescence

Reproductive Axis

GnRH

Pituitary

Reproduction

Gonads

Laser-captured single digoxigenin-labeled neurons of

gonadotropin-releasing hormone types reveal a novel

G protein-coupled receptor (Gpr54) during maturation

in cichlid fish.

single cell

KisspeptinGPR54

GnRH cell

PARHAR et al (2004), Endocrinology.

GnRH

Kisspeptin GnIH

GPR54 GPR147

GRER

Steroids

Reproduction

Pituitary

Gonads

Soga, Parhar et al (2012) Neuroscience

Parhar et al (2013) Prog Neurobiol

Soga, Parhar et al (2014) Endocrinology

GnIH neurons

3V

Kisspeptin neurons

InflammationMetabolic factors StressAge

Parhar et al (2016) Front. Endocrinol.

Cognition, Depression, Emotion

Reproduction

Kisspeptin and GnIH in hippocampus

Kisspeptin modulates sexual and

emotional brain processing in humans.

J Clin Invest. 2017

Kisspeptin enhances memory and

mitigates memory impairment induced

by Aβ1-42. Neurobiol Learn Mem. 2015

Kisspeptin ? a possible drug-candidate

for mental and cognitive disorders.

J Neurol Neurophysiol 2015

Effects of GnIH on Oxytocin Release

and Anxiety-Related Behaviour in Rats

Journal of Neuroendocrinology,2010

Estrogen,

Testosterone

Activin, Inhibin

Early life Growth and Development

• Cell division

• Cell differentiation

• Cell death (apoptosis

Fetal

aging

Reproduction

Menopause/ AndropauseLater life

GnRH

LH/FSH

Brain(hypothalamus)

Pituitary

Reproduction

Gonads

GnIHKisspeptin

HYPOTHALAMIC-PITUITARY-GONDAL AXIS

Senescent phenotype

Neurodegenerative disease