Transcript Document

Bi / CNS 150
Lecture 23
Friday November 22, 2014
Neurodegenerative diseases
Bruce Cohen
Kandel, Chapters 43, 44 (p. 1002 - 1012), 59
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Neurodegenerative Diseases
•
Neurodegenerative diseases are characterized by an abnormal loss of
neurons that begins in middle age or later and progressively increases until
death
•
They are not considered part of normal aging
•
Neurodegenerative diseases typically result in the formation of atypical, subcellular protein assemblies such as amyloid plaques, neurofibrillary tangles,
or lewy bodies
•
The three most common neurodegenerative diseases are Alzheimer disease
(AD), Parkinson’s disease (PD), and Amyotrophic lateral sclerosis (ALS)
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Alzheimer’s Disease
Initially described by Alois Alzheimer in 1901
Disease progression
I.
Starts with memory loss and impaired cognitive abilities
II.
Middle stage,
I.
individuals may forget how to do simple tasks, like brushing their
teeth or combing their hair
II.
They can no longer think clearly
III.
have problems speaking, understanding, reading, or writing.
III.
IV.
Late stage, patients become anxious or aggressive, or wander away
from home.
Eventually, patients need total care.
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Age is major risk factor for Alzheimer’s disease (AD)
AD is the most common degenerative brain disease (est. 5 million USA, 25 million globally)
The major risk factor is age
•
65-74
75
80
>85
~5%
~10%
~20%
~50%
AD is not considered normal aging (even though 50% of people older than 85 show signs)
•
Most common form of AD (late-onset or sporadic AD) occurs late in life without obvious
inheritance pattern.
•
Several risk factor genes may interact to cause the disease.
•
Most common genetic risk factor for late-onset AD is inheritance of a particular type of
apolipoprotein E (apoE) called ApoE4 (prevalence ~ 16%), two copies of which produce a 3-4 fold
dominant increase.
•
Familial AD, which is rarer, starts at age 30 - 60.
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Cytological Hallmarks of Alzheimer’s Pathology:
Amyloid Plaques and Neurofibrillary Tangles in Brain
•Amyloid plaques contain large amounts
of 42 amino acid peptide termed “bamyloid”, or Ab42
•b-amyloid itself causes initial
pathophysiology that leads to dementia
• Amyloid plaques probably contribute to
the later stages of pathology
•Neurofibrillary tangles are rich in cytoskeletal proteins,
especially the microtubule-associated protein, “tau”.
•In tangles, there are heavily phosphorylated proteins
which may cause aggregation and precipitation of the
cytoskeleton.
Also, AD reduces brain volume, especially in entorhinal cortex and hippocampus
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Presenilin 1 and APP mutations are associated with familial AD
presenilin 1 is part of
-secretase, a membrane-associated protease
Hardy and Selkoe, 2002, Science
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AD pathophysiology caused by proteolytic products from APP called Aβ40 and Aβ42
•β-APP is amyloid precursor protein.
•APP proteins are 10 to 140 kDal.
•APP expressed by most tissues, especially neurons
•Found in axon terminals, dendrites, and glial cells.
Overproduction of Ab40 and Ab42 results from altered ratio of proteolytic cleavages at sites termed a, b, and .
Kandel et al.,Principles of Neural Science
© McGraw-Hill Professional Publishing
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Genetic risk factors for AD increase accumulation of Aβ peptides
Chromosome
Gene defect
Phenotype
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β-APP mutations
↑All Aβ peptides, or Aβ40 peptides
A673T is an APP
mutation that is
neuroprotective for AD
↓ Aβ peptides, AD, cognitive decline
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ApoE4 polymorphism
(ε4 allele)
↑Density of Aβ plaques & vascular deposits
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Presenilin 1 mutation
↑Production of Aβ42 peptides
1
Presenilin 2 mutation
↑Production of Aβ42 peptides
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TREM2
↑Density of Aβ plaques
“Aβ (especially Aβ42) microaggregates—also termed “soluble Aβ oligomers” or “Aβ-derived
diffusible ligands” (ADDLs)—constitute the neurotoxic species that causes AD” – Sheng,
2012
Abnormal states of tau mediate some effects of β-amyloid. This stage may be distal to the
more toxic dimers and oligomers.
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Soluble Aβ oligomers block induction of long-term potentiation
Wild Type
CM
(Injected into ventricles 10 min
before high frequency stimulation of
the rat Schaffer collateral pathway).
CM = “conditioned medium” from a
cell line engineered to express Aβ
CM + Aβ oligomers
CM + Antibody against Aβ
CM + nonspecific
“control” antibody
Walsh et al., Nature 2002
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Parkinson’s disease
James Parkinson, apothecary surgeon described "paralysis agitans” from
observations of 6 individuals during his daily walks in London in An Essay on the
Shaking Palsy (1817)
Classic motor symptoms:
tremor at rest 3-5 Hz, “pill-rolling”
slow movements, particularly when initiating locomotion
short, rapid steps
Dramatization of the motor problems in a PD patient
http://www.youtube.com/watch?feature=endscreen&v=j86omOwx0Hk&NR=1x
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Selective loss of dopaminergic neurons in the human brain causes motor signs of PD
Substantia Nigra:
Dopaminergic neurons die in PD
Rodent brain section, stained for tyrosine hydroxylase: coronal view
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Flow chart of motor system hierarchy
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The Basal Ganglia: Major inputs
“striatum”
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Basal ganglia-thalamocortical circuit
•Basic wiring of basal ganglia
•Cortical neurons excite medium spiny neurons
(MSNs) in Putamen (upper right)
•MSNs receive modulatory input from dopaminergic
neurons in Substania Nigra pars compacta (SNc)
•MSNs are GABAergic and inhibit neurons in the
Globus Pallidus internal (Gpi) and external segments
(GPe)
•Dopaminergic input to MSNs leads to inhibition of
GPi neurons and disinhibits thalamic and
pedunculopontine neurons
•Disinhibition of these neurons allows voluntary motor
movements
•Loss of dopaminergic neurons in SNc impairs
initiation of voluntary movement
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Intracellular “Lewy bodies” in dopaminergic neurons
are hallmark of PD pathology
Lewy bodies can also occur in other diseases such as
frontotemporal dementia
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a-synuclein has an unknown function; it’s an “intrinsically disordered protein”.
Mutant a-synuclein forms fibrils.
The hallmark of PD pathology:
Intracellular “Lewy bodies”, especially in dopamine neurons
Improper mitochondrial fission / fusion
may be an early event
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PD treated with L-dopa
HO
H2
C
NH3+
CO2-
enzyme:
decarboxylase
HO
levodopa, “L-dopa”
zwitterion
permeates into brain
via a transporter
HO
H2
C
C
H2
NH3+
HO
dopamine
does not enter brain
Used with carbidopa,
which inhibits decarboxylase.
Prevents hydrolysis in the blood and in the peripheral
nervous system.
D2 receptor agonist is often added. This seems to reduce dyskinesias
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•Deep brain stimulation
for Parkinson’s disease
•Stimulting electrode placed in
subthalamic nucleus (STn)
•Tuned to frequencies that
inactivate STn activity
Nestler, Hyman, Malenka,
Molecular Neuropharmacology,
© McGraw-Hill
Professional Publishing
https://www.youtube.com/watch?v=a_4_DvquSYQ
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Bruce Cohen’s office hours,
1:15-2 328 Kerckhoff
1. Alzheimer’s disease (AD) produces overall loss of neurons
2. AD causes formation of amyloid plaques
3. Accumulation of soluble Aβ oligomers appears to cause neuronal damage in AD
4. Parkinson’s disease (PD) creates problems with voluntary motor movements
5. Motor symptoms in PD due to loss of dopaminergic neurons in SNc
6. PD causes formation of Lewy bodies in neurons
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