Thomas Arendt Paul Flechsig Institute of Brain Research University of Leipzig, Germany Alzheimer´s disease - an evolutionary perspective “Nothing in biology makes sense except in the light of evolution” (Th. Dobzhansky) 3 rd Alzheimer’s Focused #C4CT Concussion Awareness Summit at United Nations
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Thomas ArendtPaul Flechsig Institute of Brain Research
University of Leipzig, Germany
Alzheimer´s disease -
an evolutionary perspective
“Nothing in biology makes sense except in the light of evolution”(Th. Dobzhansky)
3rd Alzheimer’s Focused #C4CT Concussion Awareness Summit at United Nations
secretases
COOHNH2
loss of synapsesAß-peptide
Prevailing concepts amyloid cascade hypothesis
PSEN1/2 & APP FAD mutations
Aß-aggregates
hyperphosphorylation and aggregation of tau-protein
APP
Aß-plaques
neurofibrillary tangles
Neuronal dysfunction and death
Cerebralization:accelerated brain growth in hominid evolutionincrease in:
Why do we get Alzheimer´s disease ?
1500 cm3
1000 cm3
500 cm3
brain volume
million years-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0
Homo sapiens
Homo erectus
Australopithecus afarensischimpanzee
• AD is unique to human• major genetic risk factor: ApoE polymorphism is unique to human
• extended duration of cell cycle• more total rounds of cell division
Achilles heel• increased risk of mitotic errors• special requirements of differentiation control
Re-expression of cell cycle markers in AD
CDK 4
cyclin D
p27Kip1
p16INK4a
p18INK4c
G1
S
M
G0
cell death CDK4cyclin D
p16INK4a
p27Kip1
cyclin A p27Kip1
CDK1
p18INK4c
CDK5
cyclin E
cyclin A
CDK 1
cyclin E
Gärtner et al. Neuroreport (1995)Arendt et al. Hoppe Seyler (1993), Neurorep. (1995), Neurosci. (1996)
10µm
2n 4n
Mosch et al. J.Neurosci. 2007; Arendt et al. Am.J.Pathol. 2010
Chromosom 7Chromosom 17
10µm
The human brain is a mosaic with hyperploid neuronsThe human brain is a mosaic with hyperploid neurons
controlAD
30
4
8
12
hybr. spots
*
*
4
(%)
Slide based cytometry
Lenz et al. Progr.Biomed.Opt.Imaging 2004, 5322:146-56.Mosch et al. Cytometry A. 2006, 69:135-8Mosch et al. J. Neurosci. 2007, 27:6859-67Arendt et al. Int. J.Mol.Sci. 2009, 10:1609-27
AD: 50% increase in single cell DNA content
AD 29% 1.1%Control 12% 0.4%
0
10
20
30
40
4n
10
20
30
40
10
20
30
40
2n - 4n
*
*
num
ber o
f neu
rons
[%]
PCR amplification of alu repeats
0
10
20
30
0
10
20
30
rela
tive
frequ
ency
(%)
AD
control
4n
2n
single-neuron DNA content (pg)
2n
controlAD
control preclinical AD
mild AD severe AD
CDR 0 0 0.5 3
Braak 0 I-II B
III-IV B-C
V-VI C
CERAD normal possible probable definite
NIA negative low-intermediate
Intermed. high
Arendt et al. Am.J.Pathol. 2010, 177: 15-20
Hyperploidy is an early (preclinical) event
controlpreclinical ADmild ADsevere ADnu
mbe
r of h
yper
ploi
d ne
uron
s (m
m-2
)
disease progression
Arendt et al. Am.J.Pathol. 2010, 177: 15-20
Hyperploidy occurs prior to cell deathHyperploidy occurs prior to cell death
'Dr. Jekyll & Mr. Hyde concept'Is the risk of a phylogenetic regression based on the persistence ofdevelopmentally primitive aspects in a highly developed biological system.
non-neuronal dividing cells
(e.g. fibroblasts)
loss of neighbouring cells
loss of contaction inhibition
proliferation
tissue repair
postmitotic neurons
(non-dividing)Cellular evolution:synapse formation on the expense of the ability to proliferate
Regression:loss of synaptic input is mis-regarded as loss of contact inhibition
triggers ancient programm of repair that involves cell cycle activation
network re-organisation
re-activation of proliferation
neuronal death
functional deafferentation
Hibernation: a model for repeated cycles of synaptic regressionHibernation: a model for repeated cycles of synaptic regression600
400
200
0
40
35
30
25
20
15
10
586420
time (h)
met
ablo
icra
te (m
lO2
h-1 )
hear
t rat
e (B
MP)
body
tem
pera
ture
(°C
)
sep oct nov dec jan feb mrt
40
30
20
10
body
tem
pera
ture
(°C
)
0
euthermic torpor arousal
spin
e de
nsity
(spi
nes/
µm)
metabolic rate depression
body temperature
energy expenditure
reversible „brain shrinkage“
metabolic rate depression
body temperature
energy expenditure
reversible „brain shrinkage“
AD (PHF)-like phosphorylation of tau in hibernation
Brown bear (Ursus arctos)
European ground squirrel
Arendt et al. J.Neurosci. (2003)Härtig et al. Eur.J.Neurosci. (2007)
Stieler et al. (2008), Stieler et al. PlosOne (2011)
euthermic torpor arousal
Arctic ground squirrel(Spermophilus parryii)
pS202+pT205 (AT8)
NeocortexHippocampusCerebellumMidbrainBrainstem
Linking metabolic depression (diabetes ?) to AD-type pathology
Hamster (Cricetinae)
euthermic torpor longtorpor short arousal short arousal long
Accumulation of PHF-tau at postsynaptic sites coincideswith synaptic detachement of excitatory afferentation
0
2x105
lesionvolume(mm)
3
lesi
onvo
lum
e(µ
m3 )
p16I
NK
4ain
duce
dp1
6IN
K4a
repr
esse
d
1x105
0
2x105
lesionvolume(mm)
3
lesi
onvo
lum
e(µ
m3 )
p16I
NK
4ain
duce
dp1
6IN
K4a
repr
esse
d
1x105
Blocking cell cycle activation by p16INK4A is neuroprotectiveBlocking cell cycle activation by p16INK4A is neuroprotective
conditional (tet), neuron-specific (CamKII) expression of p16INK4A
protects against NMDA- induced cell deathconditional (tet), neuron-specific (CamKII) expression of p16INK4A
protects against NMDA- induced cell death
p16INK4A Fluoro-Jade B
INK4A
INK4A
300µm
no lesion
no lesion
NMDA
NMDA
B300µm
no lesion
no lesion
AA 300µm
p16
in
duce
dIN
K4A
p16
re
pres
sed
INK
4A
p16INK4A Fluoro-Jade B
INK4A
INK4A
300µm
no lesion
no lesion
NMDA
NMDA
B300µm
no lesion
no lesion
AA 300µm
p16
in
duce
dIN
K4A
p16
in
duce
dIN
K4A
p16
re
pres
sed
INK
4Ap1
6
repr
esse
dIN
K4A
expression of the transgene excitotoxic cell death
cell death
S
G0
G1
M
p16INK4a
CDK4
Arendt 2000; 2003
lesion volume (µm3)
p16I
NK
4Ain
duce
d
p1
6IN
K4A
repr
esse
d
ischemic cell death (middle cerebral artery occlusion; MCAO)
5
0
4
3
2
1
lesi
on v
olum
e (m
m3 )
MC
AO
+ p
16 re
pres
sed
MC
AO
+ p
16 in
duce
d
*
late
ralis
atio
n (%
)
MC
AO
+ p
16 re
pres
sed
MC
AO
+ p
16 in
duce
d
no M
CA
O
*
0
20
40
60
80
100
Expression of p16INK4a as universal mechanism of neuroprotection
MC
AO
+ p
16IN
K4A
repr
esse
dM
CA
O +
p16
INK
4A in
duce
d
lesion volume
(mm3)lateralisation
(%)
1mm
MCAO + p16INK4A repressed
MCAO + p16 INK4A induced 1mm1mm
MCAO + p16INK4A repressed
MCAO + p16 INK4A induced 1mm1mm
MCAO + p16INK4A repressed
MCAO + p16 INK4A induced 1mm1mm
MCAO + p16INK4A repressed
MCAO + p16 INK4A induced 1mm
MC
AO
+ p
16IN
K4A
repr
esse
dM
CA
O +
p16
INK
4A in
duce
d
no M
CA
O
Arendt 2000; 2003
p16INK4A
injection side
anti‐p16
Fluoro-Jade
Fluoro-Jade
anti‐p16
NMDA-inducedneurone death(Fluoro-Jade)
1mm
1mm 1mm
A
Lesi
on v
olum
e [%
]
0
10
20
30
*
p<0.01
Our vision: neuroprotection by gen-transfer of p16INK4AOur vision: neuroprotection by gen-transfer of p16INK4A
Stieler et al. Neuroreport (2001) 12:3969-3972
Cell cycle dysregulation on peripheral lymphocytes as diagnostic blood biomarker of ADCell cycle dysregulation on peripheral lymphocytes as diagnostic blood biomarker of AD
CD69 expression after mitogenic stimulation (PHA, 12µg/ml)FACscan flow cytometry
ADcontrol
stim
ulat
ion
inde
x
CD4+ CD19+st
imul
atio
n in
dex
CD4+ CD19+
mini mental scale
r=0.73
r=0.63
LymPro Test®AD patient
AD - patient
Normal subject
AD: MCI: control: n=43; n=14; n=18n=27; n=45
synaptic detachement & abnormal synaptic turnover
phylogenetic regression
cell cycle activation & partial DNA replication
second challenge –consuming reparative capacity
neuronal death
LymPro Test®
The evolutionary 'Dr. Jekyll & Mr. Hyde concept‘ of ADand emerging diagnostic & therapeutic targets