Visuo-spatial Memory in APP Transgenic Mice

Mark GoodSchool of Psychology

Cardiff University

• 90-95% are sporadic late-onset forms of AD• 5% are early onset - Mendelian inheritance: Mutations APP, PS1 & PS2

Early- & Late-onset Forms of AD: Amyloid hypothesis

Amyloid Cascade HypothesisHardy & Allsop (1991)

APPswe Tg2676 model

From : Kawarabayashi et al., 2001

K670N/M671L “Swedish” mutation

No cell lossNo Tangles

Within-subject Longitudinal Assessment of T-maze Performance

40

50

60

70

80

90

100

4 8 12

Age (Months)

% Correct

Tg2576

WT

Tg2576 Mice Show Age-dependent Impairment in Spatial Memory

Consistent: Spatial MemoryWatermazeRadial Arm MazeT-Maze

Arendash et al., 2001Kotilinek et al., 2002King & Arendash, 2002Westerman et al., 2002Ho et al., 2004Lesne et al., 2006

Hippocampus

Room A Room B

F F

Context/Room Discrimination II

Aged Tg2576 do not show a global non-specific learning deficit

Barnes, Hale & Good, Behav Neurosci, (2004)

Intra-maze Visual Discrimination

0102030405060708090

100

1 2 3 4 5 6 7 8

Day

Percent Accuracy

Tg2576WT

40

45

50

55

60

65

70

75

80

85

90

1 2 3 4 5 6 7

2 Day Blocks

Percent Correct

Tg2576WT

What aspect(s) of spatial memory is impaired in Tg2576 mice?

Navigation theories specify different strategies.

O’Keefe & Nadel (1978) - allocentric vs egocentric

Hippocampus Striatum

Location

Response

F

Hale & Good, 2008

Impaired Allocentric Learning but Spared Egocentric Learning in aged Tg2576 mice

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10

Session

Mean % Correct

WTResp Tg2576Resp WTPL Tg2576PL

How does the APP mutation influence spatial memory in Tg2576 mice?

Object Exploration Paradigm

Exploration reflects a mismatch between current sensory experience and a stored representation(memory) or a prior event.

1. Object Memory?

2. Object-Location Memory?

Testing Object and Location Memory in Mice

Exposure

Test

D?

10 min

10 min

0

10

20

30

40

Novel Familiar Novel Familiar Novel Familiar

2 Minutes 30 Minutes 24 hr

Mean Contact Time (s)

WT

Tg2576

0

0.2

0.4

0.6

0.8

2 Minutes 30 Minutes 24 hr

Mean Pref Ratio

WT

Tg2576

Intact Object Memory in Aged Tg2576 Mice

Hale & Good, Behav Neurosci, (2005)

Sample

Test

Object Location Memory

0

5

10

15

20

25

30

35

40

45

50

Different Same

Mean Contact Time (s)

WT

Tg2576

0

0.2

0.4

0.6

0.8

WT Tg2576

Mean Pref Ratio

Hale & Good, Behav Neurosci 2005

Impaired Object Location Memory

Dissociable components of object location memory

Object-in-place

Object-location

(Dix & Aggleton, 1999)

?Independent of object identity

a b

c d

a c

b d

Sample Test

Experiment 1

a b

c d

a

d

b

c

a b

c d

a

d

f

e

Experiment 2

a b

c d

Experiment 3b a

d c

d b

c a

a e

f d

a c

b d

Novelty

Familiar object ->

familiar location

Familiar object-> novel location

Novel objectand a novel location

a b

c d

Familiar object-> novel location

Familiar object-> familiar location

Good & Hale, Behav Neurosci. 2007

0.4

0.5

0.6

0.7

0.8

0.9

Object Novelty Familiar Object &Location

Familiar Object &Novel Location

Novel Object &Location

Mean Preference Ratio

WT Tg2576

a ef d

a cb d

Novelty Detection

Experiment 1

Good & Hale, Behav Neurosci. 2007

0.4

0.5

0.6

0.7

0.8

0.9

Object Novelty Familiar Object &Location

Familiar Object &Novel Location

Novel Object &Location

Mean Preference Ratio

WT Tg2576

a ef d

a cb d

a bc d

a cb d

Objects moved to familiar location

Experiment 1

Good & Hale, Behav Neurosci. 2007

0.4

0.5

0.6

0.7

0.8

0.9

Object Novelty Familiar Object &Location

Familiar Object &Novel Location

Novel Object &Location

Mean Preference Ratio

WT Tg2576

a bc d

a

d

b

c

a d

f

e

Objects moved to a novel location

Experiment 1 Experiment 2

Good & Hale, Behav Neurosci. 2007

0.4

0.5

0.6

0.7

0.8

0.9

Object Novelty Familiar Object &Location

Familiar Object &Novel Location

Novel Object &Location

Mean Preference Ratio

WT Tg2576

a bc d

a

d

b

c

a d

f

e

Objects moved to a novel location

Experiment 1 Experiment 2Good & Hale, Behav Neurosci. 2007

0.4

0.5

0.6

0.7

0.8

0.9

Object Novelty Familiar Object &Location

Familiar Object &Novel Location

Novel Object &Location

Mean Preference Ratio

WT Tg2576

a bc d

a

d

b

c

a d

f

e

Objects moved to a novel location

Experiment 1 Experiment 2Good & Hale, Behav Neurosci. 2007

Objects moved to novel locations

Experiment 3Good & Hale, Behav Neurosci. 2007

A B

C D

AB

CD

Sample Test

A B

C D A

B

C

D

Objects moved to familiar locations

Experiment 3Good & Hale, Behav Neurosci. 2007

Sample Test

Prediction: Tg2576 < WT: Object-> Familiar Locations Tg2576 = WT: Object -> Novel Locations

0.40

0.50

0.60

0.70

Novel Location Familiar Location

Mean Preference Ratio

WTTg2576

Specific impairment in object-in-place memory in Tg2576 mice

Experiment 3

a b

c d

b a

d c

d b

c a

a b

c d

Good & Hale, Behav Neurosci. 2007

Novel Familiar

Spared Spatial MemoryMemory for object-locations(independent of object identity)

Impaired Spatial MemoryMemory for object-in-place associations(conjunctive representation of object and place)

Computational/Anatomical Locus?

Characteristics of Object Spatial Memory in Tg2576 mice

Impairments in entorhinal/dentate gyrus inputs to the hippocampus may underlie the deficits in spatial memory in Tg2576 mice

Impairments in dentate gyrus spine density observed early during development in Tg2576 mice

Jacobsen et al., 2006, PNAS,103 (13), 5161-6

WT Tg2576

Hernandez-Rabaza, et al., , 2007

Dentate Gyrus Lesions in RatsImpairs T-maze but SparesObject Recognition andObject Location Memory

Dentate Gyrus Lesions Disrupt T-Maze but not Recognition Memory

ConclusionsProfile of learning processes in Tg2576 mice

1. Impaired place learning/navigation in Tg2576.2. Not a global cognitive impairment.3. Integration of object/landmark identity and location

information is impaired in Tg2576 mice.

SpeculationDisruption of entorhinal/dentate gyrus synaptic

connections/plasticity supporting pattern separation may be amongst the early pathological changes underlying memory impairments in AD.

Thanks to:

Karen AshePaul Chapman (GSK?)

Philip BarnesGemma Hale

ConclusionImpaired spatial memory despite intactlandmark recognition

deIpolyi, et al., 2007: Neurology, 69,986-997

Characteristics of Spatial Memory in early AD patients

MCI & Mild AD patients >70 yo

Hallway Navigation Task

0

5

10

15

20

25

30

C D B AObject Type

Mean Contact Time (sec)

Tg2576 WT

D B

C A

A B

C DPlace & Order

Good, Hale & Staal,Behav Neurosci (2007)

Episodic-like Memory is impaired in aged Tg2576 Mice

Deficit reflects impaired spatial (object-location) memory