Chapter 12: Aging â Related Memory Disorders --- Alzheimer's Disease
Chapter 12: Aging – Related Memory Disorders --- Alzheimer’s Disease
From Mechanisms of Memory, second edition By J. David Sweatt, Ph.D.
Chapter 12: Amyloid Plaques and Neurofibrillary Tangles
TABLE I: Stages of Alzheimer’s Disease AD Stage I, II
Areas First Affected
Symptoms
trans-entorhinal region
can be clinically silent;
entorhinal cortex
subtle loss of episodic memory
Area CA1
and difficulty executing complex progressive tasks; anecdotal repetition; some spatial disorientation
III, IV
entirety of
Early-stage AD;
hippocampus
loss of episodic memory, difficulty with spatial reasoning and recognition, difficulty with coherent speech and planning
TABLE I: Stages of Alzheimer’s Disease Continued V, VI
neocortex
Fully developed AD;
pronounced decline in cognition, frank dementia,
can include psychosis or depression, ultimately
a complete inability to communicate or care for themselves
Amyloid Plaques and Neurofibrillary Tangles, AD
Figure 1
Stages of Neurofibrillary Pathology in Alzheimer’s Disease
Figure 2
Key Molecules Involved in Alzheimer’s Disease Pathogenesis
Figure 3
Tau Phoshorylation Sites
Figure 4
Fragment of Amyloid Beta Peptide
A
B C Terminus
N Terminus Figure 5
Amyloid Precursor Protein (APP)
g
Figure 6
APP, A, and the Secretases
Figure 7
PS1 A246 E FAD Mutant Transgene Accelerates Amyloid Plaque Pathology of Tg2576 Mice Tg 2576
Figure 8
Tg 2576 + PS1 A246E
Effect of apoE Genotype on AD Risk
Figure 9
Reelin and ApoE Signaling --- Implications for AD
Figure 10
Table II: Selected Mouse Models for AD AD Models
Phenotypes
Mouse model Transgene
Tg2576 (APPswe)
PDAPP
human APP K670N/M671L
Plaques?
Yes
NFT's?
Minimal
Cell Death?
Minimal
Memory Deficits?
Fear conditioning (74)
695 AA splice variant
Water maze (73)
prion promotor
Forced Alternation (75)
human APP V717F
Yes
Partial (98)
Minimal
PDGF promotor
Water maze Spatial series (99) Object recognition (95)
Holeboard (95) Tg2576+JNPL 3
APPswe
Yes
Yes (100)
Minimal
?
Yes
Minimal
Minimal
Water maze (93, 101)
Minimal
Minimal
No (74)
P301L Tau TgLRND8
Human APP 670N/671L + V717F (+M146L L286V PS-1 mutant)
PS-1
several M146L, L286V
Plaques accelerated
Minimal
Table II: Selected Mouse Models for AD Cont. APP + PS-1
Tg2576 + A246E PS1
Yes
Minimal
Minimal
Exacerbated relative to Tg2576 alone (74, 102)
V717I
human APP V717I
Yes
Minimal
Minimal
Object recognition
V717I
crossed with PS-1
No
Similar (103)
knockout 3xTg-AD
Human APP (K670N/M671L) Human M146V PS1 Human P301L tau
yes
yes
Minimal
Fear Conditioning Water Maze Working Memory (114)
Table II: Selected Mouse Models for AD Cont. Relevant Molecules PS-1
Model type Knockout
Phenotype +/- developmental defects, -/- lethal; Forebrain:decreased hippocampal neurogenesis (104, 105)
ApoE
Knockout
Memory and LTP deficits (106, 107)
APP
Knockout
Hippocampal gliosis (108)
PS-2
Knockout
Modest phenotype (109)
ApoE4
Transgenic
No learning phenotype, accelerated plaque disposition when combined with APP V717F(66, 110)
Tau
Transgenic
Decreased neurogeneis, accelerate memory deficits when combined with APP/PS mutations (114)
FEAR CONDITIONING Training percent freezing
100
Wild Type n=9 PS-1 M146L n=6 APP K670N, M671L n=9 Double n=9
80 60 40 20 0 0
1
2
3
4
5
6
2 Pairings
7
Context
Cued 100
percent freezing
percent freezing
100 80 60 40 20 0
60 40 20 0
0
Figure 11
80
1
2
3
4
5
6
0
1
2
3
4
5
Microscopic Features of Alzheimer’s Disease
Blue Box 1
Cholinergic Hypothesis of Alzheimer's Disease and Current Pharmacotherapies A
B
Blue Box 2
From Wang et al. (2000) The Journal of Biological Chemistry 275: 5626-5632.
From Mechanisms of Memory, second edition By J. David Sweatt, Ph.D.
Chapter 12: Amyloid Plaques and Neurofibrillary Tangles
TABLE I: Stages of Alzheimer’s Disease AD Stage I, II
Areas First Affected
Symptoms
trans-entorhinal region
can be clinically silent;
entorhinal cortex
subtle loss of episodic memory
Area CA1
and difficulty executing complex progressive tasks; anecdotal repetition; some spatial disorientation
III, IV
entirety of
Early-stage AD;
hippocampus
loss of episodic memory, difficulty with spatial reasoning and recognition, difficulty with coherent speech and planning
TABLE I: Stages of Alzheimer’s Disease Continued V, VI
neocortex
Fully developed AD;
pronounced decline in cognition, frank dementia,
can include psychosis or depression, ultimately
a complete inability to communicate or care for themselves
Amyloid Plaques and Neurofibrillary Tangles, AD
Figure 1
Stages of Neurofibrillary Pathology in Alzheimer’s Disease
Figure 2
Key Molecules Involved in Alzheimer’s Disease Pathogenesis
Figure 3
Tau Phoshorylation Sites
Figure 4
Fragment of Amyloid Beta Peptide
A
B C Terminus
N Terminus Figure 5
Amyloid Precursor Protein (APP)
g
Figure 6
APP, A, and the Secretases
Figure 7
PS1 A246 E FAD Mutant Transgene Accelerates Amyloid Plaque Pathology of Tg2576 Mice Tg 2576
Figure 8
Tg 2576 + PS1 A246E
Effect of apoE Genotype on AD Risk
Figure 9
Reelin and ApoE Signaling --- Implications for AD
Figure 10
Table II: Selected Mouse Models for AD AD Models
Phenotypes
Mouse model Transgene
Tg2576 (APPswe)
PDAPP
human APP K670N/M671L
Plaques?
Yes
NFT's?
Minimal
Cell Death?
Minimal
Memory Deficits?
Fear conditioning (74)
695 AA splice variant
Water maze (73)
prion promotor
Forced Alternation (75)
human APP V717F
Yes
Partial (98)
Minimal
PDGF promotor
Water maze Spatial series (99) Object recognition (95)
Holeboard (95) Tg2576+JNPL 3
APPswe
Yes
Yes (100)
Minimal
?
Yes
Minimal
Minimal
Water maze (93, 101)
Minimal
Minimal
No (74)
P301L Tau TgLRND8
Human APP 670N/671L + V717F (+M146L L286V PS-1 mutant)
PS-1
several M146L, L286V
Plaques accelerated
Minimal
Table II: Selected Mouse Models for AD Cont. APP + PS-1
Tg2576 + A246E PS1
Yes
Minimal
Minimal
Exacerbated relative to Tg2576 alone (74, 102)
V717I
human APP V717I
Yes
Minimal
Minimal
Object recognition
V717I
crossed with PS-1
No
Similar (103)
knockout 3xTg-AD
Human APP (K670N/M671L) Human M146V PS1 Human P301L tau
yes
yes
Minimal
Fear Conditioning Water Maze Working Memory (114)
Table II: Selected Mouse Models for AD Cont. Relevant Molecules PS-1
Model type Knockout
Phenotype +/- developmental defects, -/- lethal; Forebrain:decreased hippocampal neurogenesis (104, 105)
ApoE
Knockout
Memory and LTP deficits (106, 107)
APP
Knockout
Hippocampal gliosis (108)
PS-2
Knockout
Modest phenotype (109)
ApoE4
Transgenic
No learning phenotype, accelerated plaque disposition when combined with APP V717F(66, 110)
Tau
Transgenic
Decreased neurogeneis, accelerate memory deficits when combined with APP/PS mutations (114)
FEAR CONDITIONING Training percent freezing
100
Wild Type n=9 PS-1 M146L n=6 APP K670N, M671L n=9 Double n=9
80 60 40 20 0 0
1
2
3
4
5
6
2 Pairings
7
Context
Cued 100
percent freezing
percent freezing
100 80 60 40 20 0
60 40 20 0
0
Figure 11
80
1
2
3
4
5
6
0
1
2
3
4
5
Microscopic Features of Alzheimer’s Disease
Blue Box 1
Cholinergic Hypothesis of Alzheimer's Disease and Current Pharmacotherapies A
B
Blue Box 2
From Wang et al. (2000) The Journal of Biological Chemistry 275: 5626-5632.
