Date post: | 05-Apr-2018 |
Category: |
Documents |
Upload: | gagandeep-gill |
View: | 221 times |
Download: | 0 times |
of 25
8/2/2019 Session 17 Molecular Mechanisms of AD 1
1/25
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
8/2/2019 Session 17 Molecular Mechanisms of AD 1
2/25
Circuits Affected in Alzheimers Disease
Basal nucleus
Septum and
DBB
Hippocampus
Cortex
8/2/2019 Session 17 Molecular Mechanisms of AD 1
3/25
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.
8/2/2019 Session 17 Molecular Mechanisms of AD 1
4/25
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
8/2/2019 Session 17 Molecular Mechanisms of AD 1
5/25
Secretase Cleavage of Amyloid
Precursor Protein (APP)
Modified from (Meredith 2005) and (Kheterpal et al. 2003)
Non-Amyloidogenic
Pathway
Amyloidogenic
Pathway
8/2/2019 Session 17 Molecular Mechanisms of AD 1
6/25
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
8/2/2019 Session 17 Molecular Mechanisms of AD 1
7/25
8/2/2019 Session 17 Molecular Mechanisms of AD 1
8/25
Presenilin is Part of-Secretase
8/2/2019 Session 17 Molecular Mechanisms of AD 1
9/25
A Aggregation Pathway
Modified from (Meredith 2005) and (Kheterpal et al. 2003)
Plaques
A
A
A
A
A
a
TOXIC
8/2/2019 Session 17 Molecular Mechanisms of AD 1
10/25
Amyloid Aggregation
Protofibrils
Walsh et al., 2005, Biochem Soc Trans
A42 > A40Removal via LRP1/RAGE
8/2/2019 Session 17 Molecular Mechanisms of AD 1
11/25
Tau Protein and
Neurofibrillary Tangles
Calbiochem web site
8/2/2019 Session 17 Molecular Mechanisms of AD 1
12/25
Amyloid
CascadeHypothesis
I
Protofibrils
8/2/2019 Session 17 Molecular Mechanisms of AD 1
13/25
Amyloid Cascade Hypothesis II
8/2/2019 Session 17 Molecular Mechanisms of AD 1
14/25
Multiple Isoforms of Human TauMicrotubule-binding domain
(Ballatore et al., Nature Reviews Neuroscience, 2007).
8/2/2019 Session 17 Molecular Mechanisms of AD 1
15/25
Tauopathies
(Hasegawa, Neuropathology, 2006)
8/2/2019 Session 17 Molecular Mechanisms of AD 1
16/25
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
8/2/2019 Session 17 Molecular Mechanisms of AD 1
17/25
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)
8/2/2019 Session 17 Molecular Mechanisms of AD 1
18/25
Therapeutic Strategies for
Alzheimers Disease - A
BDNF
Raise
BDNF
leve ls
8/2/2019 Session 17 Molecular Mechanisms of AD 1
19/25
APP
Regulated Intramembrane Proteolysis (RIP)
IntracellularExtracellular
A AICD
NICD
Nucleus ?
8/2/2019 Session 17 Molecular Mechanisms of AD 1
20/25
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).
8/2/2019 Session 17 Molecular Mechanisms of AD 1
21/25
Therapeutic Strategies - Tau
Gong CX, Iqbal K. (2008) Curr Med Chem.15:2321-8.
8/2/2019 Session 17 Molecular Mechanisms of AD 1
22/25
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
8/2/2019 Session 17 Molecular Mechanisms of AD 1
23/25
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
8/2/2019 Session 17 Molecular Mechanisms of AD 1
24/25
Antioxidant Diet Plus Environmental
Enrichment (EA) Significantly Decreased
Errors in a Spatial Memory Task
8/2/2019 Session 17 Molecular Mechanisms of AD 1
25/25
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