Session 17 Molecular Mechanisms of AD 1

8/2/2019 Session 17 Molecular Mechanisms of AD 1

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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


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Circuits Affected in Alzheimers Disease

Basal nucleus

Septum and

DBB

Hippocampus

Cortex


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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.


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GENETIC ALTERATIONS LEADING

TO ALZHEIMER'S DISEASEGene Chromosome Onset

APP 21 Early

TRISOMY 21 --> VERY EARLY A DEPOSITION

PRESENILIN 1 14 Early

PRESENILIN 2 1 Early

APO-E 19 Late

(E4 earlier than E3)

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


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Secretase Cleavage of Amyloid

Precursor Protein (APP)

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

Non-Amyloidogenic

Pathway

Amyloidogenic

Pathway


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KM DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK

KM NL

111

*

4042

L P

A G

EQ

G

1 11 16 40 4219 2122

Bace2

I V

* * * **

VI

FG

L

M V

Bace2

49

-secretase -secretase -secretase

V

TA

I

Mutations in Amyloid Precursor Protein


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Presenilin is Part of-Secretase


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A Aggregation Pathway

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

Plaques

A

A

A

A

A

a

TOXIC


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Amyloid Aggregation

Protofibrils

Walsh et al., 2005, Biochem Soc Trans

A42 > A40Removal via LRP1/RAGE


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Tau Protein and

Neurofibrillary Tangles

Calbiochem web site


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Amyloid

CascadeHypothesis

I

Protofibrils


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Amyloid Cascade Hypothesis II


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Multiple Isoforms of Human TauMicrotubule-binding domain

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


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Tauopathies

(Hasegawa, Neuropathology, 2006)


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Mechanisms of Toxicity in

Alzheimers DiseaseMutation in APP, PS-1/ApoE4 allele/other?

Amyloid- accumulation

Phosphorylated tau accumulation

?

Synaptic dysfunction

Memory loss

InflammationReactive oxygen speciesMitochondrial dysfunctionLoss of trophic support


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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 familyhistory and medication interactions)

Neurological/physical exam Blood tests to rule out vitamin and mineraldeficiencies and other causes

Brain scan (MRI or PiB imaging) CSF (low Amyloid-beta, high tau)


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Therapeutic Strategies for

Alzheimers Disease - A

BDNF

Raise

BDNF

leve ls


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APP

Regulated Intramembrane Proteolysis (RIP)

IntracellularExtracellular

A AICD

NICD

Nucleus ?


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Different secretase complexescontainingdifferentPresenilin

orAph1proteinsubunitsarepresentinvarioustissues.

Aph1B secretase complexesarefunctionalandstructurally

distinctrelativetotheAph1A secretase complexes.

BothcomplexessupportAICDandNICDproduction

Aph1AcomplexesarecrucialforNotchsignalling during

embryogenesis,whereasAph1B secretase complexesproduce

A142

SpecificinactivationoftheAph1Bsecretase inamouse

modelimprovesAlzheimer'ssymptomswithoutNotchrelated

sideeffects(Serneels etal.,Science,May2009).


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Therapeutic Strategies - Tau

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


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Decreased BDNF occurs early in

Alzheimers disease and is correlated withcognitive 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.

i i O i


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Antioxidant diet

+ Enriched

environment

5

10

15

*p = .005

Enriched

environment

BDN

FmRNAcop

ynumber\50n

gRNA

(X103)

Antioxidant

diet

Control

conditions

Young

canines

Old

canines

BDNF is Reduced in Old Dogs but is

Increased by Antioxidant Diet and

Environmental Enrichment

*p = .026

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

A ti id t Di t Pl E i t l


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Antioxidant Diet Plus Environmental

Enrichment (EA) Significantly Decreased

Errors in a Spatial Memory Task


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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

Session 17 Molecular Mechanisms of AD 1

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