Transcript Lecture-24-2012-Bi

Bi / CNS 150
Lecture 24
Monday November 26, 2012
Two neurodegenerative diseases
Henry Lester
Kandel, Chapters 43 & 58
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Proposal for Bi/CNS 150 extra credit:
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Result: at least 1/3 grade (i. e., B+ to A-). Retroactive, will not destroy the curve.
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2
Parkinson’s disease
1. Clinical description
2. Genetics
3. Pathophysiology
4. Biomarkers and animal models
5. Heterozygote advantage: none known
6. Therapeutic approaches
James Parkinson, apothecary surgeon
1817, An Essay on the Shaking Palsy, described "paralysis agitans",
from observations of 6 individuals during his daily walks in London
Parkinson’s disease
(tremor at rest 3-5 Hz, “pill-rolling”,
slow movements, particularly when starting;
short, rapid steps)
but most Parkinson patients are either medicated or stimulated
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Dopaminergic neurons in the human brain: Saggital view
Substantia Nigra:
Dopaminergic neurons die in PD
Ventral tegmental area:
Dopaminergic neurons remain healthy
Rodent brain section, stained for tyrosine hydroxylase: coronal view
4
like several previous Lectures
Only dopaminergic neurons express the cell membrane dopamine transporter.
Antidepressants
(“SSRIs” = serotoninselective
reuptake inhibitors):
Prozac
Zoloft
Paxil
Attention-deficit
disorder medications:
Ritalin
Dexedrine
Drugs of abuse:
Cocaine
Amphetamine
Drugs of abuse:
MDMA
Na+-coupled
cell membrane
serotonin
transporter
Na+-coupled
cell membrane
dopamine
transporter
cytosol
HO
NH
N
H
+
3
synaptic
cleft
HO
HO
H2
C
C
H2
NH
+
3
5
dopamine
Parkinsonism in people
HO
H2
C
C
H2
NH
+
3
HO
1.
Most cases are unexplained
2.
The “frozen addict”. An impurity in synthetic heroin.
Taken up by the dopamine transporter (expressed only in dopaminergic cells).
Kills cells.
3.
The influenza pandemic (worldwide epidemic) of 1918, killed 20 million people.
The flu specifically killed dopaminergic neurons in many people (“Awakenings”).
4.
Genetics: see next topic
5.
Smoking protects against PD.
reactive:
oxidative damage?
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3. Genetics. Familial Parkinson’s Disease Provides a Good Review of Bi 8/9
(~ 10% of patients). Onset 30’s to 50’s (rarely earlier or later)
Chromosome
location
Gene or protein name
Inheritance
pattern
PARK1 &
PARK4
4q21–q23
a-synuclein
(Unknown function)
AD
PARK2
6q25.2-q27
Parkin
E3 Ubiquitin ligase
AR
PARK3
2p13
Unknown
AD, IP
PARK5
4p14
UCH-L1
ubiquitin-C-terminal hydrolase-L1
AD
PARK6
1p35-p36
PINK1, PTEN-Induced Putative Kinase 1
AR
PARK7
1p36
DJ-1
AR
PARK8
12cen
LRRK2
leucine-rich repeat kinase 2
AD
PARK9
1p36
ATP13A2
AD
PARK10PARK16
Various
Much less is known
various
Locus
AD, autosomal dominant; AR, autosomal recessive; IP, incomplete penetrance
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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 one of the early events
(Prof. D. Chan, Caltech)
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4. Animal Models for Parkinson’s Disease:
Drosophila that overexpress synuclein
1. The 4 dopaminergic neurons
die preferentially!
We don’t know why.
(2. The cells show dense structures
like Lewy bodies)
3. The flies show a
“movement disorder”
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4. More Animal Models for Parkinson’s Disease
a. Toxin-treated mice, rats, and moneys;
b. Mice with altered PARK genes
c. Stem cells from people carrying PD mutations
Induced pluripotent stem cells, “disease in a dish”.
But there are still major technical issues in generating dopaminergic
neurons.
10
like previous lectures
Deep brain stimulation for Parkinson’s Disease
Tremor arises in a
malfunctioning
feedback loop:
substantia nigra,
striatum, and other
structures in basal
ganglia.
Cortex
INs
ACh
Implanted stimulating
electrodes retune this
loop.
INs
?
MSN D2R MSN D1R
Indirect
pathway
INs
dorsal
striatum
Direct
Pathway
ACh
SNc
=
Thalamus
GPe
PPTg
Axons
passing through
GPi
STN
?
SNr
Excitation
(Regardless of color)
Transmitters
ACh
GABA
Glu
+
DA
Inhibition
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Inadvertent neuroprotective effect: tobacco use
Pools
1. Meta-analysis of 45 studies
case cohort all
2
Relative
risks
1
0
Hernan, 2002
individual studies: case-control
cohort
2. Tanner, 2002: 33 discordant identical twins including at least one smoker. The twins
without PD smoked more than their brothers smoked (37.1 vs 25.3 pack-years, p=0.077)
http://en.wikipedia.org/wiki/Case-control_study
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Mechanistic hypotheses about the neuroprotective effects of tobacco use in PD
Goal: intervene in early-stage PD
with drug taken from that point.
1. Circuit-based:
Cell-selective upregulation of α4β2
nicotinic receptors
(pharmacological deep brain stimulation)
2. Presynaptic:
Selective upregulation in
nerve terminals of dopaminergic neurons
3. Cell-delimited:
Pharmacological chaperoning
of intracellular receptors
→ reprogram cell physiology
(Lester research group)
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Transplantation of stem cells induced to release dopamine
No reproducible success to date.
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Alzheimer’s disease
1. Clinical description
2. Genetics
3. Pathophysiology
4. Biomarkers and animal models
5. Heterozygote advantage: none known
6. Therapeutic approaches
1. Symptoms of Alzheimer’s Disease
1.
AD begins with a “pure” impairment of cognitive function.
2.
Progression
A.
B.
C.
AD begins slowly. At first, the only symptom may be mild forgetfulness.
In this stage, people may have trouble remembering recent events,
activities, or the names of familiar people or things.
They may not be able to solve simple math problems.
They may begin to repeat themselves every few minutes in
conversation.
In the middle stages of AD, individuals may forget how to do simple
tasks, like brushing their teeth or combing their hair.
They can no longer think clearly.
They begin to have problems speaking, understanding, reading, or
writing.
Late stage: AD patients may become anxious or aggressive, or wander
away from home.
Eventually, patients need total care.
Incidence and public health costs of Alzheimer’s disease
AD is the most common degenerative brain disease (est. 4.5 million Americans)
Risk Factors: age
65-74
75
80
>85
~5%
~10%
~20%
~50%
(However, AD is not considered a normal part of aging).
The more common form of AD, known as late-onset or sporadic AD, occurs later in life,
with no obvious inheritance pattern.
However, several risk factor genes may interact with each other to cause the disease.
Most common risk factor gene identified so far for late-onset AD, is a gene that makes
one form of apolipoprotein E (apoE). ApoE4 is the risk factor gene.
Familial AD, a rare form, usually starts at age 30 - 60.
Estimated public health cost of AD: ~ $90 billion / yr in medical care & lost productivity.
The Anatomical Hallmark of Alzheimer’s Pathology:
Amyloid Plaques and Neurofibrillary Tangles in Brain
Amyloid Plaques
contain large amounts of a 42
amino acid peptide termed
“b-amyloid”, or Ab42
The best present hypothesis:
b-amyloid itself is the initial
cause of the pathophysiology
that leads to dementia.
Amyloid plaques probably
contribute to the later stages
of pathology
Neurofibrillary tangles: rich in cytoskeletal proteins,
especially the microtubule-associated protein named
“tau”.
In the tangles: heavily phosphorylated proteins,
which may cause aggregation and precipitation of the
cytoskeleton,
2. All known genetic risk factors predisposing to Alzheimer’s disease
increase accumulation of Aβ peptides
Chromosome
Gene defect
Phenotype
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β-APP mutations
↑All Aβ peptides, or Aβ40 peptides
A673T↓ Aβ peptides, AD, cognitive decline
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ApoE4 polymorphism
(ε4 allele)
↑Density of Aβ plaques & vascular deposits
14
Presenilin 1 mutation
↑Production of Aβ42 peptides
1
Presenilin 2 mutation
↑Production of Aβ42 peptides
6
TREM2
↑Density of Aβ plaques
β-APP = amyloid precursor protein = APP
More on the latest genomic hit, TREM2
TREM2, odds ratio 2.9; frequency 0.5% in controls.
TREM2, single-pass membrane protein, expressed in immune
cells including microglia. Decreased and increased TREM2 leads
to lower and greater phagocytosis, respectively, of apoptotic
neurons.
Increased TREM2 leads to lower innate immune response.
TREM2 malfunction leads to Nasu–Hakola disease, rare recessive
disease that is with painful bone cysts in wrists and ankles,
psychotic symptoms, and progressive presenile dementia with
onset in the fourth decade of life.
Johnsson et al New Eng J Med 2012
Guerreiro et al New Eng J Med 2012
3. Pathophysiology. Aβ40 and Aβ42 are proteolytic products formed from APP
APP proteins: 110 to 140 kDal.
APP expressed by most tissues, especially neurons; reaches axon terminals and dendrites.
APP is also found in glial cells.
Overproduction of Ab40 and Ab42 results from altered ratio of proteolytic cleavages
at sites termed a, b, and g.
Fig. 58-6
Red circles: presenilin 1 and APP mutations associated with familial AD
presenilin 1 is part of
g-secretase, a membrane-associated protease
Hardy and Selkoe, 2002, Science
Normal function
of presenilin’s g-secretase activity:
Notch signaling?
APP cleavage would be a
“side effect”
Soluble Oligomers of Aβ42
Aβ42 peptides form soluble oligomers of ~4 to 40 peptides.
These oligomers interact with other proteins and precipitate to form amyloid plaques.
Soluble oligomers of Aβ42 (containing ~12 to 40 peptides) are toxic to neurons.
The 12-mer is the most significant toxic form.
Soluble oligomers block induction of LTP
(Injected into ventricles 10 min
before high frequency stimulation of
the rat Schaffer collateral pathway).
Wild Type
CM
CM + Aβ oligomers
CM = “conditioned medium” from a
cell line engineered to express Aβ
CM + Antibody against Aβ
CM + nonspecific
“control” antibody
Walsh et al., Nature 2002
Hypothetical pathophysiological sequence: APP or presinilin → familial AD
Sporadic Alzheimer’s
appears to result from
gradual failure of
clearance of Aβ.
From Selkoe, 2002, Science
4.
Biomarkers for AD: none established.
Only an autopsy is conclusive
Some progress in two areas:
1. CSF analyses of tau, phospho-tau at position181, and Aβ42.
Individual values, or ratios among these.
2. A positron emission tomography (PET) marker,
[18F]Florbetapir,
binds to plaques containing β-APP.
Animal models:
mice overexpressing APP, especially with AD-associated mutations.
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5. Heterozygote advantage: none known
6. Therapeutic approaches
Acetylcholinesterase inhibitors
(because cholinergic basal forebrain neurons are among the first to die in AD)
Aricept, Exelon, Reminyl
NMDA inhibitors
Memantine
Failed therapeutics:
Anti-APP or Aβ antibodies;
γ-secretase inhibitors
Still in development
β-secretase inhibitors
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Henry Lester’s “office” hours,
Monday this week 1:15-2
Red Door
End of lecture
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APP and its human mutations that lead to increased Ab peptides
Selkoe, Physiol. Rev., 2001
One Current Hypothesis
1. Soluble oligomers of A-b bind to
synaptic sites
a) ADDL’s (12-mer and below)
b) Ab*56 (12 mer)
2. Binding leads to internalization of
AMPA and NMDA receptors.
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
3. Activity increases amount of APP
and A-b. Are these events part of a
normal homeostatic mechanism that
becomes deranged in AD?
From J. Neurosci. (2007) 27: 11832