Transcript Alzheimer`s Disease

Alzheimer’s Disease
Lou haiyan（娄海燕）
Institute of Pharmacology
School of Medicine
Shandong University
[email protected]
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Senile Dementia (老年性痴呆症)
 Alzheimer’s disease (AD) :70%
 Vascular dementia (VD)
 Mixing dementia
 Others
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Alzheimer’s Disease
 Alzheimer disease (AD)
is the most common
cause of dementia in the
elderly. It is a progressive
neurodegenerative
disorder and associated
with the selective
damage of brain regions
and neural circuits critical
for memory and cognition
Dr.Alois Alzheimer,
diagnosed Alzheimer’s
disease in 1907
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History--The Case Auguste Deter
 This 51 y.o. woman was
admitted to Frankfort hospital
in 1901 for progressive
dementia.
 She was under the care of
Dr. Alzheimer until her death
in 1906. He did an autopsy,
examined her brain &
described the typical
abnormalities of what would
be called later Alzheimer’s
Disease.
Auguste Deter. first described
patient with Alzheimer's Disease.
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History, Continued
 This case did not prompt
any reaction untill
Kraepelin, in 1910,
referred to it as
“Alzheimer’s Disease”
(presenile dementia) in
the 8th edition of his
psychiatry book
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Incidence
65y
75y
85y
95y
5.0%
19%
47%
90%
Course of disease
3-15 years
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Examples
 您的老伴儿经常把钥匙放错地方，最近还
常常拿着钥匙却不知往门锁上插，不知用
来干什么。
 您的祖父每天喜欢在附近散步。但上个月
他有四次迷路了，要不是有邻居帮助，根
本找不到回家的路。
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AD statistics
• AD is the most common
cause of dementia among
people age 65 and older.
• Around 4.5 million people
have AD in US
• Lancet: there will be one
AD every 6 sec
• The fourth leading cause
of death in the US
• For every 5-year age
group beyond 65, the
percentage of people with
AD doubles.
• By 2050, 13.2 million older
Americans are expected to have
AD if the current numbers hold
and no preventive treatments
become available.
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Etiology
Risk Factors
Strongest risk factors
 Age
 Genetic influences(Chromsome 14,19,21
abnormalitis) such as Down’s syndrome
(Trisomy 21)
 Weaker risk factors
 Level of education, intellect or mental activity
 Female gender
 History of head injury

Initial Symptoms
 The initial symptoms include mild
forgetfulness and having trouble
remembering recent events, activities, and
the names of people.
 The AD patient might not be able to solve
simple math problems.
 These symptoms may not be enough to
cause alarm.
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Advanced Symptoms
 As the disease progresses the symptoms are
more easily noticed.
 The AD patient might forget how to brush their
teeth or comb their hair.
 They may not be able to think clearly and may
fail to recognize familiar people or places.
 People with AD can become anxious or
aggressive or wander away from home.
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Pathological Features
 Brain shrinkage (脑萎缩)
 Senile plaque (SP, 老年斑, β-淀粉样蛋白沉积)
 Neurofibrillary tangles (NFT, 神经元纤维缠结)
 Selective death of neuron
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Pathological Features
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Pathological Features
病理变化：淀粉样蛋白沉淀
Senile plaques (purple)
Normal
AD
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The amyloid hypothesis
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Amyloid Plaque Formation
 Alzheimer’s patients show numerous plaques which
are composed of 4 kD Amyloid-beta (Aβ) peptides,
which are derived from beta amyloid precursor
proteins (APPs)
 APP is a membrane associated glycoprotein of 110135 kDa that is proposed to normally behave in the
brain as a cell surface signaling molecule
 A-beta peptides are generated by endoproteolytic
cleavage of APP by Beta, alpha, and gamma
secretases
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The amyloid phypothesis
Beta-amyloid Plaques
1.
Amyloid precursor protein (APP) is the
precursor to amyloid plaque.
1. APP sticks through the neuron
membrane.
2.
3.
2. Enzymes cut the APP into fragments
of protein, including beta-amyloid.
3. Beta-amyloid fragments come together
in clumps to form plaques.
In AD, many of these clumps form,
disrupting the work of neurons. This
affects the hippocampus and other areas
of the cerebral cortex.
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The tau and tangle hypothesis
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The tau and tangle hypothesis
Neurons have an internal support structure partly made up of
microtubules. A protein called tau helps stabilize microtubules. In AD,
tau changes, causing microtubules to collapse, and tau proteins clump
together to form neurofibrillary tangles.
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Summary of mechanism of Alzheimer’s Disease
Abnormal APP metabolism
Abnormal phosphorylation of tau
b amyloid deposition
Neurofibrillary tangles
Fibrilisation
Plaque formation
Cell loss
Glucose
hypometabolism
Neurotransmitter deficits
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Cholinergic hypothesis
 Acetylcholine (Ach) is
an important
neurotransmitter in
areas of the brain
involved in memory
formation
 Loss of Ach activity
correlates with the
severity of AD.
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Genetics of Alzheimer’s disease
The two main types of AD are
early-onset and late-onset:
• Early-onset AD is rare, usually
affecting people aged 30 to 60
and usually running in families.
Researchers have identified
mutations in three genes that
cause early-onset AD.
• Late-onset AD is more common.
It usually affects people over
age 65. Researchers have
identified a gene that produces a protein called apolipoprotein E (ApoE).
Scientists believe this protein is involved in the formation of beta-amyloid
plaques.
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 Early-onset AD
 Chromosome 21: APP
 Chromosome 14 and 1: presenilin-1 and 2
 Late-onset AD
 Chromosome 19: apoE
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Other Causes of AD
• Oxidative damage from free radical
molecules can injure neurons.
• AD has a neuroinflammatory component
• Abnormal glycation of proteins (AGEs) and AD
• A study shows that an elevated level of
homocysteine is associated with increased
risk of AD.
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Treatment of AD
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Cholinesterase inhibitors
Glutamatergic agents
Antioxidants
Non-steroidal anti-inflammatory drugs
Reduction of risk factors
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1. AChE-inhibitors

Tacrine

Huperzine A
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Donepezil

Rivastigmine

Galantamine
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1. AChE-inhibitors
Tacrine (他克林)—first generation
1. inhibit AChE（selectivity is low）
2. excite M-R, N-R
3. promote ACh release (due to M1-R)
4. promote glucose use
Adverse reaction: hepatotoxicity, (withdrawn)
periphery Ach effect
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 Huperzine A（石杉碱甲）
 Donepezil (多奈哌齐）
 Rivastigmine(利斯的明）--Second generation
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
Fewer side effects than tacrine
Mild to moderate AD
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2. Glutamatergic agents
Memantine (美金刚）
 Uncompetitive NMDA receptor antagonist
 Significantly slow down the rate of cognitive
and functional decline
 Synergistic effect with AChE inhibitors
 The first drug approved by FDA to treat severe
AD
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3. Potentiator of neuronal growth factor
Neotrofin (AIT 082)
Propentofylline (丙戊茶碱）
Blastic fibric growth factors（成纤维细胞生长因子,
bFGF）
Neuronal growth factors（NGF）
Brain derived nutrition factors（BDNF）agonist
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4. Brain metabolism activator ：
Piracetam (吡拉西坦)
5. M-R agonist：
Xanomeline（占诺美林）
----selective M1-R agonist
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The Search for New Treatments
Researchers also are looking at other treatments:
• Cholesterol-lowering drugs called
statins
• Anti-oxidants
• Anti-inflammatory drugs
• Substances that prevent formation
of beta-amyloid plaques
• Nerve growth factor to keep
neurons healthy
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Thanks
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