Transcript Alzheimer`s Disease: Genetics, Pathogenesis, Models, and

Alzheimer’s Disease: Genetics,
Pathogenesis, Models, and
Experimental Therapeutics
[Auguste Deter, Alois Alzheimer's patient in
November 1901, first described patient with
Alzheimer's Disease.]
[1864 - Dr. Alois Alzheimer, psychiatrist,
pathologist, born in Marktbreit, Bavaria]
Causes of dementia
Definitions
Dementia – a general term for a group of disorders that cause irreversible
cognitive decline as a result of biological damage to brain cells
Alzheimer’s disease (AD) –the most common dementia, accounting for 50-70
percent of cases
Other forms of dementia include
•Vascular dementia
•Parkinson’s disease
•Dementia with Lewy bodies
•Frontotemporal dementia
•Creutzfeldt-Jakob disease
•Normal pressure hydrocephalus
Alzheimer’s disease = Alzheimer’s disease and related dementias
Clinical features and Laboratory studies
•
Alzheimer disease (AD) is the most common form of dementia and usually
occurs in old age.
•
It is invariably fatal, generally within ten years of the first signs.
•
Normal aging involves forgetfulness but the early signs of AD include
unusual memory loss.
(remembering recent events and the names of people and things)
•
As the disease progresses the patient exhibits more serious problems.
(subject to mood swings and unable to perform complex activities such as
driving.)
•
In the latter stages they forget how to do simple things and then require fulltime care.
Neuropathorogy and Biochemistry of AD
• Neuropathology
– Alzheimer's disease is characterised by loss of neurons and
synapses in the cerebral cortex and certain subcortical regions.
– This loss results in degeneration in the temporal lobe and
parietal lobe, and parts of the frontal cortex.
– Reductions in the size of specific brain regions in patients as
they progressed from mild cognitive impairment to Alzheimer's
disease.
Both amyloid plaques and neurofibrillary tangles are clearly visible by
microscopy in brains of those afflicted by AD.
– Plaques are dense, mostly insoluble deposits of amyloid-beta
peptide and cellular material outside and around neurons.
– Tangles (neurofibrillary tangles) are aggregates of the microtubuleassociated protein tau which has become hyperphosphorylated and
accumulate inside the cells themselves.
Neuropathorogy and Biochemistry of AD
• Biochemistry
– Enzymes act on the APP (amyloid precursor protein) and cut it
into fragments. The beta-amyloid fragment is crucial in the
formation of senile plaques in AD.
– AD has been identified as a protein misfolding disease, caused by
accumulation of abnormally folded A-beta and tau proteins in the
brain.
– Plaques are made up of small peptides, 39–43 amino acids,
called beta-amyloid (also written as A-beta or Aβ).
• fragment from a larger protein called APP, a transmembrane
protein that penetrates through the neuron's membrane.
• (APP: neuron growth, survival and post-injury repair)
Neuropathorogy and Biochemistry of AD
• Biochemistry
– In Alzheimer's disease, an abnormal aggregation of the tau
protein lead to the disintegration of microtubules in brain cells.
• Tau protein(microtubule-associated protein) stabilizes the
microtubules when phosphorylated.
• In AD, tau becoming hyperphosphorylated; creating
neurofibrillary tangles and disintegrating the neuron's transport
system.
Genetic: Familial AD and risk factors
The majority of cases of Alzheimer's disease are sporadic
– not genetically inherited although some genes may act as risk factors
– around 0.1% of the cases are familial forms of autosomal-dominant
inheritance
Autosomal dominant familial AD can be attributed to mutations in one of
three genes: amyloid precursor protein (APP) and presenilins 1 and 2.
– Mutations in the APP and presenilin genes increase the production of a
Aβ42.
The best known genetic risk factor is the inheritance of the ε4 allele of the
apolipoprotein E (APOE).
– Between 40 and 80% of patients with AD possess at least one apoE4 allele.
– Therefore the APOE4 allele increases the risk of the disease.
APP and PS families of proteins
Familial Alzheimer disease is caused by mutations in at least 3 genes:
•
PSEN1 - Presenilin 1 (PSEN1 located on chromosome 14)
– Mutations in this gene cause familial Alzheimer's type under 50 years
old.
– This protein has been identified as part of the enzymatic complex that
cleaves amyloid beta peptide from APP.
•
PSEN2 - Presenilin 2 (PSEN2 located on chromosome 1)
– The presenilin 2 gene is very similar in structure and function to PSEN1.
•
APP – Amyloid beta (A4) precursor protein
– Processing of the amyloid precursor protein
– Mutations to the amyloid beta A4 precursor protein (APP) located on the
long arm of chromosome 21 causes familial Alzheimer disease.
APP and PS families of proteins
• Secretase
– BACE1
• β-amyloid cleaving enzyme1
• This transmembrane aspartyl protease is directlly involved in
the cleavage of APP at the sites of Aβ in APP.
– γ-secretase
• This multiprotein catalytic complex includes PS1 and PS2;
nicastrin (Nct), a type 1 transmembrane glycoprotein; and
Aph-1 and Pen-2, two multipass transmembrane protein.
Processing of APP by secretases
Genetic models of Aβ amyloidosis
and AD-linked taupathies
• Aβ amyloidosis
– Amyloid beta is a peptide of 39-43 amino acids
– Main constituent of amyloid plaques in the brains of Alzheimer’s
disease patients.
– Aβ is proteolytically derived from a larger integral membrane
protein, the amyloid precursor protein (APP).
• AD-linked taupathies
– Taupathies are a class of neurodegenerative diseases resulting
from the pathological aggregation of tau protein in so-called
neurofibrillary tangles (NFT) in the human brain.
Targeting of genes encoding
amyloidogenic secretases
To understand the function of some of the proteins thought to have roles in
AD: targeted a variety of genes including BACE1, PS1, Nct, and Aph-1.
•
BACE1-/- Mice
– BACE1 is a key enzyme in the generation of the Aβ peptide that plays a
central role in the pathogenesis of Alzheimer's disease.
•
PS1-/- Mice
– PS1 knock-in mice exhibited NFT-like tau pathology in the absence of Aβ
deposition.
– PS1 mutations contribute to the onset of AD not only by enhancing Aβ1–42
production but by also processing that lead to neurodegeneration.
Clinical approaches to Alzheimer’s Disease
•
Cholinesterase Inhibitor
– 약물로 저하된 시냅스 간극의 뇌의 아세틸콜린 분해를 억제
– 콜린 농도를 증가시켜 뇌세포 사이의 의사소통을 회복
– Tacrine, Donepezil, Rivastigminne, Galantamine
•
NMDA Antagonists
– 중등도 및 중증의 알츠하이머병 환자에서 기억력을 안정시키는 효과
– Glutamate가 작용하는 NMDA 수용체가 활성화 되는 것 방지
– Memanitn
•
β- and γ-secretase Inhibition and γ-secretase Modulation
– Toxic peptide Aβ42의 레벨을 감소시켜주는 γ-secretase의 선택적 조절
– Flurizan
Conclusions
It is anticipated that discoveries during the next
few year will lead to the design of new
mechanism-based therapies that can be tested
in animal models, and, eventually, these
approaches will be introduced successfully into
the clinic for the benefit of patients with this
devastating illness.
Thank you
Referance
• http://www.youtube.com/watch?v=9Wv9jrk-gXc
• http://www.kmle.co.kr/search.php?Search=Alzheimer+disease&Page=3
• http://blog.naver.com/hanhosp?Redirect=Log&logNo=130095137523
• http://blog.naver.com/hanhosp?Redirect=Log&logNo=130095137523
• Alzheimer disease. (Castellani RJ et al., 2010)
• Alzheimer's disease neurofibrillary degeneration: pivotal and
multifactorial. (qbal K et al., 2010)