Transcript gr dvl

• AGING and DEMENTIAS
• Canonical changes during aging
• Classification of dementias
• Symptoms of dementia
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ALZHEIMER'S DISEASE
Clinical manifestations
Cellular pathology
Cholinergic deficits, relationship between cholinergic loss,
pathological lesions and dementia
Other neuropathological-neurochemical abnormalities
Progression of the disease
Pathology of the aging brain in relation to AD
Clinical-pathological correlations
Aethiology and pathogenesis
Therapy in AD
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From Adams and Victor, 1993
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a: Diffuse β-amyloid deposits in the frontal cortex stained
with monoclonal antibody 4G8 x 50. Braak and Braak
b: Primitive plaque without central amyloid core or
dystrophic neurites. Modified Bielschowsky silver stain x
200. Braak and Braak.
c: Classical plaque with central amyloid core and peripheral
crown of dystrophic neurites. Modified Bielschowsky stain
x 200 . Braak and Braak.
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a: forms of extracellular BA protein deposits. b: neuritic plaques, tangles and neuropil threads. c: first traces of tangle
material, d: the mature tangle fills the cell body, e: extraneuronal ‘ghost’, f-m: neurofibrillary tangles in different cell
types of the hippocampus, n: tangle-bearing isocortical layer IIIab-pyramidal cell, o: ghost tangle in CA1. Silver
technique. Braak and Braak.
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a: Jellinger, 1990; Mioyoshi and Sato, 1991; b :
Manns et al., 1991; c: Masliah et al., 1991; d:
Xuereb et al., 1991
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Maps of rostro-caudal cholinergic neurons (stained with the antibodsy against choline acteyltransferase) in serial 40
um coronal sections of the basal forebrain in human. Ch1-Ch4 nomenclature according to Mesulam. From Lehericy
et al. 1999
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Maps of coronal sections in the
human brain. ChAT staining. From
Lehericy et al
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Summary of the major pathways for cholinergic innervation of the cortical mantle by the
magnocellular basal complex (Saper, 1990).
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(Geula and Mesulam, 1994)
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Mean density of neuritic plaques in 5 neocortical regions
as a function of dementia severity. (Haroutunian et al.,
1998)
Median of ratings of neuritic plaque density using
the neuropathological battery of the CERAD.
0=absent; 1=sparse; 3= moderate and 5=severe in
the hippocampus, entorhinal cortex and amygdala.
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Density of neurofibrillary tangles in four neocortical regions and in the entorhinal cortex, hippocampus and
amygdala in non-demented (CDR score 0), questionable ( CDR= 0.5), moderately (CDR=2) and demented
(CDR=5) subjects. The y axis represents the median of Consortium to Establish a Registry for Alzheimer’s
Disease (CERAD) neurofibrillary ratings (0 indicates none; 1 sparse; 3=moderate and 5=severe).
(Haraoutuniqan et al., 1999)
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AChE-positive cholinergic fibers in layer III of the auditory assoc.
cortex of a 71 year old normal person and of a 67-year old patient
with AD. This region displays severe loss of cholinergic neurons,
accompanied by a high density of plaques and tangles (NFT).
ACHE-positive cholinergic fibers in LIII of the cingulate cortex of a
normal person and of a 67-year old patient with AD. The cingulate
cortex shows a remarkable preservation of cholinergic fibres, however,
this area contains high density of amyloid plaques and tangles. (Geula
and Mesulam, 1994)
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Geual and Mesulam, 1994
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Activity of ChAT in 9 cortical regions as a function of dementia severity Relative to the group without dementia
(CDR score=0), the activity of ChAT was significantly reduced (p<0.001 for all) in the CDR 5.0 group only. BA
indicates Brodmann area. (Davis et al., 1999)
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Correlation of ChAT activity in the superior temporal gyrus (Brodmann area 22) with
neuirtic plaque density (left chart) and neurofubriallary tangle density (right chart) for
the entire cohort. (Davis et al., 1999)
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A
B
Thioflavin S-stained neurofibriallary
tangles in layer II of the entorhinal
cortex in AD. These neurons give rise
to major component of the perforant
pathway that links the cortex with the
dentate gyrus.
Alz-50 terminal immunoreactivity in the
outer two thirds of the molecular layer of
the dentate gyrus in an area that would
correspond to the terminal zone of the
perforant pathway. This pattern of
immunoreactivity suggests that the AD
antigen recognized by Alz-50 is located
in the terminals of LII entorhinal
neurons. Note the presence of Alz-50
immunoreactive neuritic plaques in the
immunoreqactive zone. The vessel
marks the location of the hipp. Fissure.
The granule cells of the dentate gyrus
(SG) have been stained with thopnin.
(G. van Hoesen)
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Distribution of neurofibrillary tangles in the auditory cortex
from a case of AD. Note the primary auditory coretx
(Brodmann’s area 41 and 42 is largely spared. The dorsal
and lateral parts of area 22, the sensory association cortex,
are also relatively spared. More distal auditory association
areas in the upper bank of the superior temporal sulcus
contain extensive pathology (Mesulam)
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Development of neurofibrillary tangles and neuropil
threads from transentorhinal to isocortical stages.
Increasing density of shading indicates increasing
severity of the pathological changes. (Braak and Brrak,
1994)
Neuropathological staging of AD-related changes in
the anteromedial portion of the temporal lobe, (Braak
and Braak, 1994).
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Summary diagrams of
neurofibrillary changes seen
in anteromedial portions of
the temporal lobe and
development of changes
from stage I to stage VI of
AD. Fd=fascia dentata;
gr=granula, mo=molecular
layer. CA1: m=molecular;
p=pyramidal; o=oriens;
a=alveus. (Braak and Braak,
1994)
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Summary diagram of neurofibrillary
changes seen in the occipital cortex in
stages III-VI of AD. Left, various
architectonic schemes to show the
laminar pattern in the striate (core),
parastriate (belt) and the peristriata
association cortex (Braak and Braak,
1994
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Hof and Morrison, 1994
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a
b
Simplified diagrams of connections between the isocortex and
subcortical ‘centers’ of the motor cortex (a); connections between
imortant centers of the ‘limbic’ system (b) and diagram of
connections between the isocortex and ascending subcortical
modulatory centers (Braak and Braak, 1994).
c
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Predilection sites for
amyloid deposits (b)
and neurofibrillary
changes. Compare
with Plate 28 for
identification of
boxes. (Braak and
Braak, 1994).
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A
A: Domain structure and functional map of APP
showing location of the BA4 region (shaded).
The APP-770 transcipt includes a Kunitz protease
inhibitor-motif (from Hardy).
B: Schematic showing the BA domain, residing
partially in the transmembrane, partially
extracellularly. Note the alfa and Beta-secretase
cleavage sites and the positions of APP mutations
linked to familial AD. Cleavage at residues 40
and 42 is thought to be the result of the gammasecretase (from D. Price).
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A
B
A: APP mutation helix. The relationships between mutation
sites and the cleavage sites are indicated. Gray area:
membrane (Hardy). B: Schematic drawing showing the
cleavage sites of the alfa, Beta and gamma-secretase and the
resulting fragments. The left side shows the APP, the right
the Notch proteolytic processing. sAPP= soluble APP, CT=
C-terminus fragment; Tr sAPP=truncated sAPP;
p3=fragment. ANK, LN, EGF = different Notch domains
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Hypothetical scheme to show the APP-metabolite-induced toxicity through the disruption of ionic balance. APP is processed through the
Golgi apparatus and is either (1) metabolized to sAPP, CT and BA fragments and released from the cell or (2) transported to and
incorporated into the membrane as full-length APP. (3) APP might be cleaved to release sAPP or (4) might be transported to the
endosomes or lysosomes. Intracellular CT fragments and BA might (5) form ion channels in the cell membrane or (6) puncture holes in
Ca2+ stores. Both actions could result in ionic imbalance and cell damage (7-8), leading to cell death through apoptosis or necrosis. BA
fragments released from the cell could modulate surrounding transportes (10), ionic pump or exchangers (11), receptors (12) ion channels
(13) and form de novo ion channels (14). (Fraser et al).
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Notch and APP proteolytic processing. The domain structure of murin Notch 1 and human APP717/770
are indicated. APP and Notch are drawn approximately to scale. The regions that are important for
proteolytic processing are magnified and the amino-acid sequences are displayed using the one-letter
code. Notch 1 is cleaved in the ectodomain by furin, while APP is cleaved by alfa and B-secretase. Both
proteins are cleaved in their transmembrane domain by a gamma-secretase-like activity that is controlled
by presinilin. Asterisks indicate the localization of mutations in the APP and preseilin-1 sequence.
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Schematic drawing showing the 8 transmembrane domain topology of PS1 (blue), APP (yellow) and Notch 1 (red). The
endoproteolytic cleavage site of PS1 is indicated bt red arrow and the proposed crucial aspartates (D257 and D385) are indicated
by red dots. The intramembranous clevage sites in APP and Notch 1 are indicated by blue arrows and regions corresponding to
carboxyl-terminus fragments (CTF) and the Notch intracellular domain (NICD) are also indicated. Note that APP is cleaved at
multiple sites by gamma-secretase, whereas cleavage of Notch 1 occurs at single site. Pink and blue arrows indicate the furin and
TACE sites in the Notch 1 ectodomain and black arrows the alfa and Beta secretase sites in the APP ectodomain
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Cartoon (Science, 294,
1296, 2001) showing
that cholesterol secreted
by astrocytes bound to
large lipoprotein
particles containing
apoE. These particles are
internalized by neurons,
leading increased
cholesterol within
neuronal membranes.
Cholesterol is needed to
activate signaling
pathway that triggers
synaptogenesis –either
an apoE receptor
pathway or another
signaling pathway such
as the sonic hedgehog,
Wnt cascades.
Alternatively, a
sufficient amount of
cholesterol itself might
be needed to support the
structural demands of
synaptogenesis.
1992
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In the amyloid-cascade hypothesis, the deposition of B-amyloid protein in brain parenchyma is the pivotal event. Bamyloid deposition can be triggered by mutations in the gene encoding the APP or by binding to apoE4. B-amyloid
deposition then leads to the formation of neuritic plaques, NFts and nerve cell death (Hardy, 1992).
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A possible mechanism fro the spread of focal
B-amyloid deposition in AD (Hardy, 1992)
The relationships between BA and tau and between AD and FTDP-17
(front-temporal dementia). The link between BA42 overproduction and
tau dysfunction is presently uncertain and represented by a ? mark. In
addition, it is unclear whether tau dysfunction leads directly to cell death
or if the formation of NFTs are a necessary intermediate (Hardy, 1998).
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?
The tau and tangle hypothesis. Tau binding to microtubules is disrupted by phosphorylation, directly by mutations that alter isoform
expression. Decreased tau binding to microtubules might result in increased free tau which, under the appropriate conditions will selfaggregate to form insoluble paired helical filaments. ? Mark indicates the putative role of amyloid induced increased GSK-3
(glycogen synthethase kinase) activity that leads to increased tau phosphorylation (From Mudher and Lovestone, 2002).
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The wnt signalling hypothesis. Wnt transduces a signal through dvl and protein kinase C (PKC). Wnt and dvl increase secreted sAPP and
inhibit glycogen synthase kinase 3 (GSK-3B) phosphorylation of tau. Both processes might be normal. Loss of wnt signal would result in
decreased sAPP, increased tau phophorylation and both pathological hallmarks (plaques and tangles) of AD. JNK, c-Jun N-terminal kinase;
MAPK, mitogen-activated protein kinase (Mudher and Lovestone, 2002)
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C
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A: Anatomical organization of major perforant pathway innervation of
hippocampus by axons originating in LII of the ipislat entorhinal cortex.
B: Disruption of perforant pathway causes changes in synaptic density
in the outer two thirds of the dendrites of the dentate granule cells.
Curves show approximate times for mRNA expressions for GFAP (glial
fibrillary acidic protein), SGP2 (sulfated glycoprotein), vimentin,
apolipoprotein (apoE), alfa1 tubulin, TGF-B (transforming growth
factor) in the dentate gyrus (Finch and Day, 1994).
C: Multiple factors increase the neuroplasticity burden. Eventually the
excessive neuroplasticity burden triggers plaque and NFT formation
(Mesulam, 1999)
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•
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Cholinergic basal forebrain (BF) neurons (a) in
normal physiological conditions and (b) as postulated
in individuals with AD. In cholinergic neurons of the
BF in individuals with AD, ChAT immunoreactivity,
cell size and number, and NGF and TrkA levels are
decreased. In the hippocampus of individuals with
AD, ChAT levels and ACh-mediated signaling are
reduced but NGF levels are increased or unchanged.
In the hippocampus and BF of individuals with AD,
APP expression and A aggregate levels are
increased, whereas secreted (trophic) sAPPs are
decreased. There are also degenerating terminals in
the hippocampus. These altered levels indicate that
NGF retrograde transport or NGF binding to trkA
receptors, or both, are reduced in the individuals with
AD, which results in inappropriate trophic support of
the cholinergic system during degenerative disease
A: amyloid ; ACh, acetylcholine; AD, Alzheimer's
disease; APP, amyloid precursor protein; ChAT,
choline acetyl transferase; DS, Down's syndrome;
NGF, nerve growth factor; sAPP, soluble APP; TrkA,
tyrosine receptor kinase A.
(Isacson et al., 2002)
Potential Treatments for Alzheimer’s Disease
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Potential Treatments of AD (cont.)