The Last FrontiersRobert Lyn Nelson

The Last FrontiersRobert Lyn Nelson

Alzheimer’s Alzheimer’s DiseaseDisease

BRAIN,THE FINAL FRONTIER

BRAIN,THE FINAL FRONTIER

The Last FrontiersRobert Lyn Nelson

The Last FrontiersRobert Lyn Nelson

Kiminobu Sugaya, Ph.D.

Alzheimer’s DiseaseAlzheimer’s Disease

Amyloid- precursor protein

NHNH22 COOHCOOHAA

-amyloid deposition-amyloid deposition

PlaquesPlaques

-secretase

Normal Normal Secretory Secretory PathwayPathway

-secretase-secretase

Mechanism of Neurodegeneration in Alzheimer’s DiseaseMechanism of Neurodegeneration in Alzheimer’s Disease

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Glial Activation in Aging and DiseaseGlial Activation in Aging and Disease

Age

Gli

al A

ctiv

atio

n (

Infl

amm

atio

n)

Gli

al A

ctiv

atio

n (

Infl

amm

atio

n)

Neuronal Dysfunction or Neurodegeneration

Neuronal Dysfunction or Neurodegeneration

ShiftShiftShiftShift

ShiftShiftShiftShift

APOPTOSISAPOPTOSIS

Cellular Fragmentation into Apoptotic Bodies

Phagocytosis and DegradationPhagocytosis and Degradation

DNA Fragmentation

Cromatin Condensation

Membrane Blebbing and Loss of Nuclear Envelope

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Aged Control

Fragmented DNA (Apoptosis) in the

hippocampus

Fragmented DNA (Apoptosis) in the

hippocampusAlzheimer’s disease

Amyloid Plaque and Apoptosis

Amyloid Plaque and Apoptosis

Plaque with many TUNEL positive cells

Plaque with many TUNEL positive cells

Plaque with a few TUNEL positive cellsPlaque with a few TUNEL positive cells

Plaque with no TUNEL positive

cells

Plaque with no TUNEL positive

cells

Neuro-fibrillary Tangles and Apoptosis

Neuro-fibrillary Tangles and Apoptosis

Astrocyte and ApoptosisAstrocyte and Apoptosis

Apoptotic CellsApoptotic Cells

AstorocyteAstorocyte

GFAP mRNA GFAP mRNA Expression in the Expression in the

Aged Memory Aged Memory Impaired Model Rat Impaired Model Rat

14.6868.42122.16175.90229.64283.38337.13390.87444.61498.35552.09605.83659.57713.31767.05820.79874.54928.28982.021035.761089.501143.241196.981250.721304.461358.201411.941465.691519.431573.171626.911680.651734.39

Young

Aged unimpaired

Aged impaired

Ci/g tissue

memory score

Rad

io a

cti

vit

y in

th

e s

ecti

on

(n

Ci/

g)

300

youngAged unimpaired Aged impaired

0

100

200

300

400

500

600

120 140 160 180 200 220 240 260 280

p=0.0001

Regression Analysis Regression Analysis of GFAP mRNA of GFAP mRNA

Expression in the Expression in the Hippocampus Hippocampus

against the Memory against the Memory ScoreScore

APP mRNA APP mRNA Expression in the Expression in the

Aged Memory Aged Memory Impaired Model Rat Impaired Model Rat

68.17176.38284.60392.81501.03609.24717.46825.67933.891042.101 150.311258.531366.741474.961583.171691.391799.601907.812016.032124.242232.462340.672448.892557.102665.322773.532881.742989.963098.173206.393314.603422.823531.03

Young

Aged unimpaired

Aged impaired

Ci/g tissue

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

120 140 160 180 200 220 240 260 280 300

memory score

Rad

io a

cti

vit

y in

th

e s

ecti

on

(n

Ci/

g)

p = 0.0055

youngAged unimpaired Aged impaired

Regression Analysis Regression Analysis of APP mRNA of APP mRNA

Expression in the Expression in the Hippocampus Hippocampus

against the Memory against the Memory ScoreScore

Mn-SOD mRNA Mn-SOD mRNA Expression in the Expression in the

Aged Memory Aged Memory Impaired Model Rat Impaired Model Rat

Young

Aged unimpaired

Aged impaired

Ci/g tissue

49.2852.1354.9757.8260.6663.5166.3669.2072.0574.8977.7480.5983.4386.2889.1291.9794.8297.66100.51103.35106.20109.04111.89114.74117.58120.43123.27126.12128.97131.81134.66137.50memory score

Rad

io a

cti

vit

y in

th

e s

ecti

on

(n

Ci/

g)

90

110

130

150

170

190

210

120 140 160 180 200 220 240 260 280 300

p = 0.0190

youngAged unimpaired Aged impaired

Regression Analysis Regression Analysis of Mn-SOD mRNA of Mn-SOD mRNA Expression in the Expression in the

Hippocampus Hippocampus against the Memory against the Memory

ScoreScore

APP ISHH with GFAP Immunostaining in APP ISHH with GFAP Immunostaining in the Aged Memory Impaired Model Rats the Aged Memory Impaired Model Rats

maturedmatured

Aged ImpairedAged Impaired Dentate GyrusHilus

Dentate Gyrus

Hilus

CA1

CA1

GFAP ISHH (astrocytes marker) with 4G8 (A) Immuno-histochemistry in PS1-APP

TM

GFAP ISHH (astrocytes marker) with 4G8 (A) Immuno-histochemistry in PS1-APP

TM

APP ISHH with GFAP Immuno-APP ISHH with GFAP Immuno-histochemistry (astrocytes marker) in PS1-histochemistry (astrocytes marker) in PS1-APP TMAPP TM

APP ISHH with 4G8 (A) Immuno-histochemistry in PS1-APP TM

APP ISHH with 4G8 (A) Immuno-histochemistry in PS1-APP TM