The human circadian timing system in aging, Alzheimer's disease and Depression

203 Pages·2006·2.21 MB·English

The human circadian timing system in aging, Alzheimer’s disease and Depression

THE HUMAN CIRCADIAN TIMING SYSTEM
IN AGING, ALZHEIMER’S DISEASE AND DEPRESSION
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctor
aan de Universiteit van Amsterdam
op gezag van de Rector Magnificus
prof. mr. P.F. van der Heijden
ten overstaan van een door het college
voor promoties ingestelde commissie,
in het openbaar te verdedigen
in de Aula der Universiteit
op dinsdag 30 januari 2007, te 12:00 uur
door
Yinghui Wu
geboren te HuangShan, Volksrepubliek China
PROMOTIECOMMISSIE
Promotores: Prof. dr. D.F. Swaab
Prof. dr. J.N. Zhou
Overige leden: Prof. dr. R.M. Buijs
Prof. dr. G.A. Kerkhof
Prof. dr. W.A. van Gool
Dr. M.P. Gerkema
Dr. G.T. J. van der Horst
Faculteit der Geneeskunde
This investigation was carried out at the Netherlands Institute for Neuroscience
with financial support from
Royal Netherlands Academy of Arts and Sciences (01CDP019, 02CDP014, 04CDP026)
National Key project for Basic Science of China (G1999054007)
Hersenstichting Nederland (11F03.07)
Netherlands Organisation for Scientific Research (NWO)
Publication of this thesis was financially supported by
Netherlands Insitute for Neuroscience
Van Leersumfonds KNAW
University of Amsterdam
Internationale Stichting Alzheimer Onderzoek (ISAO)
Stichting Onderzoek Licht & Gezondheid (SOLG)
J. E. Jurriaanse Stichting
Book design: Henk Stoffels, Amsterdam
Print: Gildeprint bv, Enschede
Contents

Chapter 1 General introduction 9
Chapter 2 Molecular changes underlying reduced pineal melatonin levels 47
in Alzheimer’s disease: alterations in preclinical and clinical stages
Chapter 3 A promoter polymorphism in the monoamine oxidase A gene 65
is associated with the increased MAOA activity in Alzheimer’s
disease
Chapter 4 Pineal clock gene oscillation is disturbed in Alzheimer’s disease, 77
due to functional disconnection from the “master clock”

Chapter 5 Distribution of melatonin receptor MT1 immunoreactivity in 95
the human hypothalamus and pituitary gland: colocalization
of MT1 with vasopressin and corticotropin-releasing hormone
Chapter 6 Decreased MT1 melatonin receptor expression in the 117
suprachiasmatic nucleus in aging and Alzheimer’s disease
Chapter 7 Increased number of neurons expressing melatonin receptor 133
MT1 in the suprachiasmatic nucleus in depression, and its
relation to age at onset and disease duration
Chapter 8 General discussion 147
References 175
Summary 210
Nederlandse samenvatting 215
List of publications 220
Acknowledgements 221

List of abbreviations 222
Curriculum vitae 224

Chapter 1
General introduction
Content
A. The circadian timing system and its molecular basis: changes in aging, Alzheimer’s disease, 9
depression and other circadian rhythm disorders
B. The human pineal gland and melatonin in aging and Alzheimer’s disease 28
C. Melatonin receptors: localization, molecular biology and physiological significance 36
D. Scope of the thesis 41
A. The circadian timing system and its molecular basis: changes in aging,
Alzheimer’s disease, depression and other circadian rhythm disorders
Partly based upon the paper: Y-H Wu, D.F. Swaab, Sleep Medicine, accepted
The past decade has been an extremely exciting and fast paced time for circadian biol-
ogy, in which the basic molecular mechanisms underlying the mammalian circadian
clock were defined. This paper reviews the circadian timing system and its molecular
components that provide the mechanisms for the regulation of circadian rhythms in
mammals including humans, and relates them to the circadian abnormalities in aging,
Alzheimer’s disease, depression and other circadian rhythm-related diseases.
The circadian timing system
Temporal variations in endocrine, metabolism, autonomic, pharmacokinetics, and in
some aspects of disease show the pervasive influence of the circadian clock on human
physiology and pathophysiology. These circadian rhythms, as they are called, are the
external expression of an internal timing mechanism that measures daily time. Cir-
cadian clocks are normally set or entrained by periodic environmental cues, with the
daily light-dark cycle as the most pervasive and potent entraining stimulus in mam-
mals. An entrained circadian clock ensures that rhythms in physiology and behavior
are in tune with the 24-h day.
Three major components are present in all circadian systems identified to date: (a) a
light input pathway to a self-sustained master circadian pacemaker, (b) the circadian
pacemaker, and (c) output pathways by which the circadian pacemaker regulates overt
rhythms in biochemistry, physiology, and behavior throughout the organism 1.
9
chapter 1
Suprachiasmtic nucleus: the “central biological clock”
In mammals, the endogenous biological circadian clock is located in the suprachias-
matic nucleus (SCN) of the anterior hypothalamus 2, 3. The SCN is situated just above
the optic chiasm, on each side of the third ventricle 4, 5. SCN neurons are not homog-
enous, but are classified according to their neuropeptide content 4, 6. A simplified
view of the rodent SCN has a core of vasoactive intestinal peptide (VIP) expressing
neurons and a surrounding shell of arginine vasopressin peptide (AVP) expressing
neurons. Both parts of the SCN each contain approximately 10,000 tightly packed
neurons in the mouse 4, and 16,000 neurons in the rat 5. In the ventrolateral part of the
rodent SCN, neurons synthesize VIP, gastrin-releasing peptide (GRP) and/or peptide
histidine isoleucine (PHI). In between these two cell populations, a distinct popula-
tion of somatostatin (SOM)-positive neurons is found. Gamma-amino-butyric acid
(GABA) is present throughout the SCN and colocalizes with the above-mentioned
neurotransmitters. In addition, many more neurotransmitters have been reported to
be present, such as galanin and antiotensin II (for review see 7).
Animal experiments have shown that lesions of the SCN abolish the locomotor
activity rhythm as well as other rhythms, while transplantation of a fetal SCN may
restore circadian activity rhythms in such lesioned animals 7-13. Interestingly, a restored
rhythm adapts to the circadian rhythm of the donor, not to that of the recipience 14.
In both night-active (nocturnal) and day-active (diurnal) mammals, most SCN
neurons are active during the daytime and inactive at night time 7, 15-17. The circadian
rhythm in metabolic activity of the SCN is also similar in diurnal and nocturnal
mammals, with a peak at midday 18. Humans and other mammals share a very similar
anatomy and physiology of the circadian system, which strongly supports the critical
role of the SCN in humans. The human SCN is also located in the anterior hypotha-
lamus, bilaterally next to the third ventricle and on top of the optic chiasm, just as in
other mammals (Fig. 1). The human SCN has similar structures and contains similar
neurotransmitters AVP, VIP and GABA to the rodent 6, 19. The AVP and VIP neu-
ropeptide show a clear circadian pattern in the human SCN 20, 21 (Fig. 2). The bilateral
human SCN is about 1 mm3 in volume and contains about 100.000 neurons 22. The
vasopressin subnucleus of the SCN has a volume of 0.25 mm3 and contains some
10.000 vasopressin neurons on each side 23. The human SCN additionally contains
neurotensin as an important neurotransmitter 19. The projections from the retina to the
human SCN and from the SCN to other brain regions of the hypothalamus in human
are very similar to those in rat 24, 25. The circadian system is functionally similar in hu-
man and other mammals, and can be phase-shifted by light and melatonin, the most
important day and night signals for the SCN, respectively 26. Finally, the importance
of the SCN for circadian rhythms in humans is revealed by clinical observations. Pa-
tients who had a lesion in the suprachiasmatic region in the hypothalamus, e.g. as the
10
general introduction
A.
B.
SCN
Fig. 1 The location of the suprachiasmatic nucleus (SCN) in the human brain. A. Midsagittal
view of the human brain. B. a thionin-stained coronal section of the human brain.
11
chapter 1
A.
0.2 mm
III
Fig. 2 A. Distribution of arginine vasopressin (AVP)-expressing and vasoactive intestinal
polypeptide (VIP)-expressing neurons in the human suprachiasmatic nucleus (SCN) in con-
secutive frontal sections. Drawing showing the distribution of the AVP neurons (dots) and
VIP neurons (circles) through the mid-portion of the SCN. B. Circadian fluctuations of the
AVP and VIP-expressing cell numbers in the human SCN. The data is represented by mean
± S.E.M. (gray area indicates S.E.M.) III: third ventricle. Top is caudal, bottom is rostral.
Modified from Hofman (2000).
result of metastasis, indeed showed a decreased expression of vasopressin in the SCN
and disturbed circadian rhythms 19, 27-29. In addition, in a patient with a hypothalamic
astrocytoma that destroyed the SCN bilaterally, disruptions of the day/night rhythm
of the wake/sleep pattern was observed 30.
Input to the SCN
The endogenous biological clock, the SCN, can function autonomously, independent
of any external time cues, but its intrinsic period is not exactly 24 h. The endogenous
circadian clock is entrained to a 24-h environmental cycle by environmental cues,
in particular light/dark cycles. Some blind people who lack the synchronizing input
12