Aging in Dogs

Elizabeth Head, Ph.D.Sanders-Brown Center on Aging

University of KentuckyLexington, KY

1. Ab sequence is

identical

2. APP sequence virtually

identical (only 21/770

aa differ on the longest

isoform = 98.4%

homologous)

3. Canine genome

published:

http://www.ensembl.or

g/Canis_familiaris/

4. Age-dependent cortical

accumulation

5. Correlated with

cognition

Ab PathologyFirst noted plaques in the brains of

aged dogs in 1956 by Braunmuhl

(silver staining)

Wisniewski et al first suggested the

dog as a model for amyloidogenesis in

1970Parietal Cortex

2 4 6 8 10 12 14 16 18 20

Am

ylo

id L

oad

(%

)

0

5

10

15

20

25

Occipital Cortex

2 4 6 8 10 12 14 16 18 20

0

5

10

15

20

25

Prefrontal Cortex

Chronological Age (years)

2 4 6 8 10 12 14 16 18 20

0

5

10

15

20

25

Entorhinal Cortex

2 4 6 8 10 12 14 16 18 20

0

5

10

15

20

25

Ab biomarkers in dogs

Head et al., 2010.

Similar to observations in AD –overall lower levels of CSF Ab 1-42

Cerebrovascular Pathology in Aging Dogs

• Cerebral amyloid angiopathy

• Typically associated with shorter more

soluble Ab1-40

• May affect vasodilation and constriction function of blood vessels

• Microhemorrhages increase with age

• Need for more imaging studies in dogs (e.g. ASL, T2*, FLAIR)

Neurobiological Changes in Aging DogsCognition declines with age

Young Old

To

ta

l N

um

be

r D

CX

/Brd

U+

Ne

uro

ns

0

500

1000

1500

2000

2500

Reduced neurogenesisReduced neuron numbers in hilus

Parietal Synaptophysin

Age

0 2 4 6 8 10 12 14 16 18

Syn

ap

top

hys

in A

dju

ste

d O

D (

raw

/ac

tin

)

0

50

100

150

200

250

Synapse protein loss with age

BD

NF

mR

NA

Co

py N

um

be

r

0

2000

4000

6000

8000

10000

12000

Young Aged

Loss of growth factorsAge Effects on Mitochondrial Generation of ROS

Time (minutes)

4 6 8 10 12 14 16

RO

S G

ene

ratio

n

0

200

400

600

800

1000

1200Young Animals

Aged Animals

p<.002

p<.002

p<.004

Mitochondrial dysfunction

Other thoughts

What dogs do not show:

• Full blown tangles – some evidence for tau phosphorylation – sequence differences – is there such a thing as canine tangles?

• Significant glial responses to Ab– is this because Ab is primarily diffuse (although fibrillar at ultrastructural level)

• Inflammation appears to not be as pronounced as in human brain although needs more systematic study

What dogs may be useful for:

• Environmental contributions to brain aging/neuropathology – e.g. pet dogs vs laboratory dogs?