Argyrophilic grain disease
Prof. Isidro Ferrer, Institut Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, CIBERNED, Hospitalet de LLobregat; Spain
B C
D E F
A
AGD: Gallyas
Argyrophilic grains (AGs)
Neurons with pre-tangles
Astrocytes with argyrophilia
Coiled bodies in oligodendrocytes
Ballooned neurons in amygdala
AGD at first: a neuropathological finding in some patients with dementia
AGs and pre-tangles are recognized with severalphospho-specific anti-tau antibodies
ARGYROPHILIC GRAIN DISEASE: DEMENTIA WITH GRAINS
Delineation of a process versus definition of a disease
Braak H. Braak E. Argyrophilic grains Characteristic pathology of cerebral cortex in cases of adult onset dementia withoutAlzheimer changes. Neurosci Lett 1987;76124-127Braak H. Braak E. Cortical and subcortical argyrophilic grains characterize A disease associated withadult onset dementia. Neuropathol Appl Neurobiol 1989;15:13-26Ikeda K, Akiyama H. Kondo H. Haga C. A study of dementia with argyrophilic grains. Possible cytoskeletal abnormality in dendrospinal portion of neurons and oligodendrocytes. Acta Neuropathol 1995;89:409-414Tolnay M, Spillantini MG, Goedert M, Ulrich J, Bangui D, Probst A. Argyrophilic Grain disease: Widespreadhyperphosphorylation of tau protein in limbic neurons. Acta Neuropathol 1997;93:477-484Tolnay M, Probst A. Ballooned neurons expressing alpha B-crystallin as a constant feature of the amygdala in argyrophilic graindisease. Neurosci Lett 1998;246:165-168
AGD: A novel tauopathy
Togo T, Sahara N, Yen SH, Cookson N, Ishizara T, Hutton M, de Silva R, Lees A, Dickson DW. Argyrophilic grain disease is a sporadic 4-repeat tauopaty. J Neuropathol Exp Neurol 2002;61:547-556Tolnay M, Sergeant N, Ghestem A, Chalbot S, de Vos RAI, Jansen Steur ENH, Probst A, Delacourte A. Argyrophilic graindisease and Alzheimer´s disease are distinguished by their different distribution of tau protein isoforms. Acta Neuropathol2002;104:425-434Ferrer I, Barrachina M, Tolnay M, Rey MJ, Vidal N, Carmona M, Blanco R, Puig B. Phosphorylated protein kinases associatedwith neuronal and glial tau deposits in argyrophilic grain disease. Brain Pathol 2003;13:62-78.
Molecular pathology of AGD
Ferrer I, Santpere G, van Leeuwen FW. Argyrophilic grain disease. Brain 2008; 131: 1416-1432
A
E F
D
B C
Grains: Golgi method
A
C
B
DAGD. A: CA1, AT8; B: laterotuberal, AT8; C: CA1, 4R; D: entorhinal cortex, 4R
AGD. A: CA1; B: dentate gyrus; C: entorhinal cortex; D: amygdala; E: accumbens; F: septum; G: putamen; H: substantia nigra; I: white matter; J: CA1 tau4R; K: EC tau4R; I: amyg, αB-crystallin
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D
CB
F
I
K
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E
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AGD cortical. A: CA1; B: amygdala; C: entorhinal cortex; D: frontal cortex
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DC
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Argyrophilic grain (AG) staging
• Stage I: anterior entorhinal cortex; mild involvement of the cortical and basolateral nuclei of the amygdala; mild involvement of the hypothalamic lateral tuberal nucleus.
• Stage II: entorhinal cortex; anterior CA1; transentorhinal cortex; cortical and basolateral nuclei of the amygdala; presubiculum; hypothalamic lateral tuberal nucleus; dentate gyrus.
• Stage III: entorhinal cortex; CA1; perirhinal cortex; presubiculum; amygdala; dentate gyrus; hypothalamic lateral tuberal nucleus; mild involvement of CA2 and CA3; mild involvement of the subiculum; mild involvement of other nuclei of the hypothalamus (i.e. mammillary bodies); mild involvement of the anterior temporal cortex, insular cortex, anterior cingulated gyrus, orbitofrontalcortex, nucleus accumbens, septal nuclei; rare grains in the midbrain.
• Stage IV: moderate to severe additional involvement of the neocortex and brainstem
Clinical symptoms
•Cognitive decline and dementia
•Behavioural abnormalities, personality changes and emotional and mood imbalance
•Episodic memory loss
•Amnesia, irritability and agitation, followed by delusions, dysphoria and apathy
•Mild amnestic cognitive impairment is not uncommon as an initial manifestation of AGD
•A small number of patients present with progressive trans-cortical sensory aphasia, prominent abnormal behaviour and aggression, and moderate to severe cognitive impairment consistent with frontotemporal dementia
The presence of AGD plus mild-moderate AD-type pathology is, probably, the cause of dementia and not just the presence of AGD.
The age of onset is around 70 years old. The duration of the disease is between 4 and 8 years
ARGYROPHILIC GRAIN DISEASE: DEMENTIA WITH GRAINS
Genetics
The disease appears to be sporadic
Not known genetic factors, but for a single hereditary case:
Kovacs GG, Pittman A, Revesz T, Luk C, Lees A, Kiss E, Tariska P, Laszlo L, Molnár K, Molnar MJ, Tolnay M, de Silva R. MAPT S305I mutation: implications for agryrophilic grain disease. Acta Neuropathol 116: 103-118 (2008)
The frequency of apolipoprotein E ε4 (ApoE ε4) allele in AGD is similar to that of the general population. Yet the frequency of ApoE ε2 is higher than that observed in AD and controls
Association of AGD with tau H1 haplotype is confusing, with both positive and negative results (Togo et al., 2002; Miserez et al., 2003).
ARGYROPHILIC GRAIN DISEASE: DEMENTIA WITH GRAINSAssociation of AGD with Alzheimer disease, progressive supranuclear palsy, Corticobasal degeneration and α-synucleinopathies
Martinez-Lage P, Muñoz DG. Prevalence and disease associations of argyrophilic grains of Braak. J Neuropathol Exp Neurol 1997;56:157-164
Braak H, Braak E. Argyrophylic grain disease: Frequency of occurrence in different age categories andneuropthological diagnostic criteria. J Neural Transm 1998;105:801-809
Ikeda K, Akiyama H, Arai T, Matsushita M, Tsuchiya K, Miyazaki H. Clinical aspects of argyrophilic graindisease. Clin Neuropathol 2000;19:278-284
Tolnay M, Monsch AU, Probst A. Argyrophilic grain disease. A frequent dementing disorder in old patients. Adv Exp Med Biol 2001;487:39-58
Togo T, Cookson N, Dickson DW. Argyrophilic grain disease: Neuropathology, frequency in a dementiabrain bank and lack of relationship with apolipoprotein E. Brain Pathol 2002;12:45-52
AGD+PSP. A: s. nigra; B: nucleus of the vagus nerve; C: reticular formation; D: CA1; E: subiculum; F: entorhinal cortex; G: dentate gyrus; H: dentate gyrus; I: amygdala
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D
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F
IH
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AGD+PSP. A: septum; B: accumbens; C: caudate; D: medial putamen; E: mammillary bodies; F: basal forebrain; G: frontal cortex; I: amygdala (tufted)
A
D
CB
F
IH
E
G
AGD+ astrocytic plaques: A: CA1; B: entorhinal cortex; C: amygdala; D: temporal cortex
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DC
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ARGYROPHILIC GRAIN DISEASE: DEMENTIA WITH GRAINS
AGD and neurotransmitters
Practically nothing known, excepting
Yamada T, McGeer PL, McGeer EG. Some immunohistochemical features of argyrophilic grain dementia with normal cortical choline acetyltransferase levels but extensive subcortical pathology and markedly reduced dopamine. J Geriatr Psychiatry Neurol 5: 3-13 (1992)
Perez-Buira S, Barrachina M, Rodriguez A, Albasanz JL, Martin M, Ferrer I. Expression levels of adenosine receptors in hippocampus and frontal cortex in argyrophilic grain disease. Neurosci Lett 423:194-199 (2007)
0,2
0,6
1,0
1,4
1,8
C AGD
A1R
pro
tein
leve
ls(A
U) *
AGDC
Hippocampus
A1R (37 KDa)
β-Actin (45 KDa)
B
A
AGDC
Frontal Cortex
A1R (37 KDa)
β-Actin (45 KDa)
0,5
1,5
2,5
C AGD
A1R
pro
tein
leve
ls(A
U)
B
AGDC
Frontal Cortex
β-Actin (45 KDa)
ACI (120 KDa)
0,5
1,5
2,5
C AGD
AC
I pro
tein
leve
ls(A
U)
A
AGDC
Hippocampus
β-Actin (45 KDa)
ACI (120 KDa)
0,5
1,5
2,5
C AGD
AC
I pro
tein
leve
ls(A
U)
*
Adenosine receptors in the frontal cortex and hippocampus in AGD
BA
D
C
E
G
F
H I
anti-tau phospho-specific antibodies Thr181 (A), Ser214 (B), Ser396 (C), Ser199 (D), Ser231 (E), Ser422 (F), Ser202 (G) and Ser262 (H), and antibody 7.51 (I)
AGD is a tauopathy with tauphosphorylated at different threonine and serine sites
S-IF Total
66
46
S-IF Total
6864
S-IF Total
6864
S-IF Total
6864
tau 7.51 Thr 181 Ser 262 Ser 422
AGD is a 4R tauopathy
4R immunohistochemistry
A B C
Active stress kinases: SAPK/JNK-P and p38-P, and GSK-3β
Several tau-kinases are localized in neurons with pre-tangles and in grains
tau-kinases co-localize with tau-P in neurons with pre-tangles and in grains
Tau 422
TotalS-IF
6864
TotalS-IF
GSK-3β-P
54
66
54
TotalS-IF
CaMKII
TotalS-IF
MAPK/ERK-P
66
4244
38
TotalS-IF
p38-P
TotalS-IF
MEK-1
45
TotalS-IF
ERK2
4250
TotalS-IF
JNK-1
TotalS-IF
GSK-3α/β
66
5147
TotalS-IF
54
66
SAPK-JNK-P
Tau kinases in sarkosyl insoluble fractions and in total homogenates in AGD
NF tau SAPK/JNK-P + tau
SAPK/JNK-P + tau
p38-P + tau
αB-crystallin, phosphorylated neurofilaments, phospho-tau and tau-kinases in ballooned neurons in theamygdala
Tau kinases and phospho-tau are also present in ballooned neurons in the entorhinalcortex and amygdala
++-++++GSK-3β-P
++++ p+++++++++P38-P
++++ p+++++++SAPK/JNK-P
++++ d++-MAPK/ERK-P
------GSK-3β
------JNK-1
------ERK
------MEK
+++++ d+++++++++Ser422
+++ p++++++++Ser396
+±++ d+++++++Ser214
++++ p+++++++Ser201
+++ p+++++++++Thr181
Coiledbodies
AstrocytBalloonedneuron
TanglesPre-tanglesGrain
αB-crystallin is phosphorylated in ballooned neurons
Specific tau truncated forms are usually encountered in AGD and they differ from those seen in AD
746864
62
AGD AGD AD
AA
B C
D E F
G H I
thrombin calpain 2 caspase 3
Thrombin is a strong candidate as a causative protease of truncated tau
B
C D
A p62
ubiquitin
The ubiquitin-proteasome system (UPS) in AGD
A B C
D E F
Ubiquitin + AT8
Ubiquitin co-localizes with tau in AGs
Blot Ab: anti-Ubi
2
3
1
4
220120100
80
60
50
40
mar
ker
ctls AGD-pat.
band
N; Human AGD-Ubiquitin
0
5
10
15
20
25
30
35
40
45
50
type of sample
dens
ity ctl
AGD-patol.
Human AGD-Ubiquitin
0
20
40
60
80
100
120
140
band1 band2 band3 band4
type of samplede
nsity ctl
AGD
p<0.0048 p<0.005
* *
Human AGD-Ubiquitin
0
20
40
60
80
100
120
140
band1 band2 band3 band4
type of samplede
nsity ctl
AGD
p<0.0048 p<0.005
* *
Increased ubiquitination in selected protein bands in AGD hippocampus
A
C
D
E
B
Mutant ubiquitin
B CAnti-CML
100
80
60
50
40
30
AGD
B123 C
E
LR
F
GO
Q
H
S
Control
A
K
100
80
60
50
40
30
A
BlotBlot AbAb:: AntiAnti--CELCEL
220
120
80
60
50
40
30
20
CTL AGD
BlotBlot AbAb:: AntiAnti--CMLCML
220
12080
60
50
40
30
20
BlotBlot AbAb:: AntiAnti--MDALMDAL
220
120
80
60
50
40
30
20
CTL AGD
BlotBlot AbAb:: AntiAnti--DNPDNP
220
120
80
60
50
40
30
20
0
20
40
60
80
100
DNP CEL CML MDAL
dens
ity a
djus
ted
to a
ctin
CTL
AGD
*
*
CEL CML MDAL0
25
50
75
100
125
150CTLAGD
*
GSA AASA0
50
100
150CTLAGD
Oxidative stress and oxidative damage in AGD
Increased expression of oxidative damage as revealed with different markers
A
C D
B
RAGE: receptor ofadvanced glycationend products
Oxidative stress responses in AGD
A, B: controlC, D: AGD
B
DC
A
SOD1: A, B: control; C, D: AGD. A, C: CA1; B, D: EC SOD2: A: control, B: AGD. CA1
BA
Oxidative stress responses in AGD
Superoxide dismutase 1 and 2: SOD1 and SOD2
CTL AGD
30
Blot Ab: Anti-NDUFS3
70
Blot Ab: Anti-SDHA
48
Blot Ab: Anti-UQCRC2
57
Blot Ab: Anti-MTCO1
57
Blot Ab: Anti-AIF
48
BlotBlot AbAb:: AntiAnti--ββ--ActinActin
BlotBlot AbAb:: AntiAnti--PorinPorin
31
36
Blot Ab: Anti-UCP4
* *
**
A
B0
0,2
0,4
0,6
0,8
1
1,2
1,4
NDUFS3 SDHA UQCRC2 MTCO1 UCP4 AIF
dens
ityad
just
edto
porin
CTLAGD
Mitochondrial respiratory complexes and AIF in AGD hippocampus
Decreased expression of proteins of mitochondrial complexes, and increased AIF
tau-P+ mitochondrial porin. No porin localization in grains
36
Blot Ab: Anti-Eif-2α
Blot Ab: Anti-pEif-2α
Blot Ab: Anti-IRE1
105
BlotBlot AbAb:: AntiAnti--ββ--ActinActin
48
Blot Ab: Anti-ATF6
90
Blot Ab: Anti-XBP1
31
36
CTL AGD
Blot Ab: Anti-ATF6 cleaved
50
A
78
Blot Ab: Anti-GRP 78
94
Blot Ab: Anti-GRP 94
Blot Ab: Anti-KDEL
9478
48
Blot Ab: Anti-PDI
BlotBlot AbAb:: AntiAnti--ββ--ActinActin
60
CTL AGDB
Increased expression of endoplasmic reticulum stress markers in AGD hippocampus
tau4R
tau hyperphosphorylation
hyperphosphorylated tau aggregation
tau ubiquination
oxidative stress oxidative responses RAGE SOD1 SOD2
activation of stress kinasesSAPK/JNK and p38
activation of otherkinases: i.e. GSK-3β
p62
ubiquitin
tau/UBB+1
impaired UPS function
mRNA misreading: UBB+1
AGs
pre-tangles
tangles
AGs
tangles
Sequestration of active stress kinases and GSK-3β
trombin in AGs andtangles
tau
truncated tau
aging mitochondrial anomalies
Endoplasmic reticulum stress
Abnormal protein folding
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