Pathological Diagnosis of Alzheimers Disease

Senile Plaques (amyloid-) Neurofibrillary Tangles (tau) Synaptic Loss: Cortex Hippocampus Basal forebrain Entorhinal cortex

Synaptic loss correlates with the degree of dementia

Circuits Affected in Alzheimers Disease

Cortex

Hippocampus

Septum and DBB Basal nucleus

Therapy of Alzheimers Disease: anticholinesterases

Aricept or Aricept + Memantine Does not prevent the continuous degeneration of neurons, the treatment being therefore symptomatic. Efficacy decreases as the disease progresses.

GENETIC ALTERATIONS LEADING TO ALZHEIMER'S DISEASE

Gene Chromosome Onset APP 21 Early TRISOMY 21 --> VERY EARLY A DEPOSITION PRESENILIN 1 PRESENILIN 2 APO-E 14 1 19 Early Early Late (E4 earlier than E3)

5% Familial, Early onset 95% Sporadic, Late onset

Secretase Cleavage of Amyloid Precursor Protein (APP)

Non-Amyloidogenic Pathway Amyloidogenic Pathway

Modified from (Meredith 2005) and (Kheterpal et al. 2003)

Mutations in Amyloid Precursor Protein

1
Bace2

11

Bace2

40

42

49

* ** V KM DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK 1 11 16 19 2122 Q G 40 42 A I T M V V I V

E KM NL A G

I L F G

-secretase

-secretase

-secretase

INS T 113 L

115 Y

116 117 T P

F T 120 E

N-TF ...
D T
123 E

Q G D K R T Y

105 F

96 V

T V A V 94 M V 92 L C 89 T V P F V 84 L M 82 83 V I H DEL K 79 A G Y K L E V V Q R T L E E D E E E D Q S N G Q P D R R S L G H P E P L S N G R N H E Q 35 R H N E 29 S R V R N D N Q 28 27 26 T N S L D E S N-TF M Q A 1 T E L P A P M L S Y F Q N

V S K I

H S I L 135 N A A I 139 M I V 143 S I V 146 M 147 V T I L L V V 153 154 L Y K INS F Y INS I R C Y K

T V G Q R

APP
T Y K F V 184 E G L I Y 178 F S F F 177174 175 F 173 L L 171 L L 169 S I S166 167 I W L A 165 DEL 163 H I V G Y E S N V A V D Y I T V A L L I W N F 206 V V 209G G M I S 213 I H W K

S E V 670 K 671 673 D M A 1 677 R F E D H secretase

K T E 665 E I

Presenilin 1

A S G D T 693 secretase E A W 694 405 D N S L P V Y T E A G K N S K T W K Lumen G I 409 I A A 410 T 246 394 237 I G A W F C F G I L 392 V L 235 V M L 233 A V A V I 250 L 390 V S L A I L I G G 40 V L M 231 F Y A V I I G 418 V 229 S I S V 713 I D F A M 226 I 384 C 420 L 42 G 256 T Y D L G V 714 716 715 L L 424 T Y L L L A V V 260 261 L secretase I T I 717 K A V L L 222 Q V L 262 426 L Q L A I 377 378 R G V 723 M F L Cytosol R 263 E C K K K 219 E L 264 ... K P K M 269 L 267 R P 271 217 P 431 L P G K G A C-TF D 272 V L 273 E E P WM 274 G T I 467 434 R N E A I A Q E 278 280 284 T L P A A 435 Y L T 285 Y M V A L E 436 282 F P L 286 S V N G L 290 D I S Q P I F S E H S S A 439 F I N Y K S N K S 318 A E 365 V R R Q S A T S T E L R L C-TF F E E S Q G Q Q D L D V M V T A F F V A P Y A 358 R Q F E S V A N E L D T P Y D D INS R 354 T G S G R F S P H E E W E A Q R D S H L G

V H H Q K L V F F 692 A

Presenilin is Part of -Secretase

A Aggregation Pathway

Plaques

A A A A a

TOXIC

Modified from (Meredith 2005) and (Kheterpal et al. 2003)

Amyloid Aggregation

Removal via LRP1/RAGE

A42 > A40

Protofibrils
Walsh et al., 2005, Biochem Soc Trans

Tau Protein and Neurofibrillary Tangles

Calbiochem web site

Amyloid Cascade Hypothesis I

Protofibrils

Amyloid Cascade Hypothesis II

Multiple Isoforms of Human Tau

Microtubule-binding domain

(Ballatore et al., Nature Reviews Neuroscience, 2007).

Tauopathies

(Hasegawa, Neuropathology, 2006)

Mechanisms of Toxicity in Alzheimers Disease

Mutation in APP, PS-1/ApoE4 allele/other? Amyloid- accumulation Phosphorylated tau accumulation
Mitochondrial dysfunction Loss ofInflammation Reactive oxygen species trophic support ?

Synaptic dysfunction Memory loss

Clinical Diagnosis of Alzheimers Disease

Psychological testing
Evaluation of activities of daily living such as managing finances and medications Mini Mental State Exam and other tests to evaluate thinking and memory Caregiver interview

Medical and psychiatric history (rule out family history and medication interactions) Neurological/physical exam Blood tests to rule out vitamin and mineral deficiencies and other causes Brain scan (MRI or PiB imaging) CSF (low Amyloid-beta, high tau)

Therapeutic Strategies for Alzheimers Disease - A

Raise BDNF levels

BDNF

Regulated Intramembrane Proteolysis (RIP)

NICD

APP

Nucleus ?
A

AICD
Intracellular

Extracellular

Differentsecretase complexescontainingdifferentPresenilin orAph1proteinsubunitsarepresentinvarioustissues. Aph1Bsecretase complexesarefunctionalandstructurally distinctrelativetotheAph1Asecretase complexes. BothcomplexessupportAICDandNICDproduction Aph1AcomplexesarecrucialforNotchsignalling during embryogenesis,whereasAph1Bsecretase complexesproduce A142 SpecificinactivationoftheAph1Bsecretase inamouse modelimprovesAlzheimer'ssymptomswithoutNotchrelated sideeffects(Serneels etal.,Science,May2009).

Therapeutic Strategies - Tau

Gong CX, Iqbal K. (2008) Curr Med Chem.15:2321-8.

Decreased BDNF occurs early in Alzheimers disease and is correlated with cognitive decline. Transgenic animals with similar BDNF decreases exhibit deficits in LTP & synaptic transmission. Delivering BDNF to the brain by infusion, viral vectors or neural stem cells rescues cognition and increases synaptic density in transgenic Alzheimers disease mice.

BDNF is Reduced in Old Dogs but is Increased by Antioxidant Diet and Environmental Enrichment
BDNF mRNA copy number\50 ng RNA (X103)

15
*p = .005 *p = .026

10

5
n=5 n=6 n=6 n=5 n=6

Young canines

Antioxidant diet + Enriched environment Antioxidant Enriched diet environment Control conditions

Old canines

Antioxidant Diet Plus Environmental Enrichment (EA) Significantly Decreased Errors in a Spatial Memory Task

Issues
Earlier diagnosis, especially biomarkers for MCI to AD conversion What is the toxic form of A? Tau? Are plaques protective? Mechanism of neurodegeneration? Transgenic mice as models