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77 Cards in this Set

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Who was the first to present the neuropathologic characteristics of alzheimer's disease 100 years ago?
Alois Alzheimer
Where in the brain does the degeneration occur in Alzheimer's disease?
In the frontotemporal lobe
What other disease did Alzheimer characterize?
Pick's disease
What are the two things that characterize the pathology of Alzheimer's?
1. Amyloid-Beta plaques
2. Neurofibrillary tangles
Where are amyloid-B plaques?
Where are Neurofibrillary tangles and what are they made of?
Amyloid-B plaques: EXTRAcellular
Neurofib Tangles: INTRAcellular (intraneuronal) - made of TAU
How is Pick's Disease similar to Alzheimer's disease?
They both have junk consisting of Amyloid-B or Tau
What are the amyloid-B containing junks in Pick's disease called? Why?
Pick bodies - they're contained in inclusions
So the main difference between Neurofibrillary tangles and Amyloid plaques is what?
Neurofib tangles - INTRAcellular
Amyloid plaques - EXTRAcellular
What is the major component of the plaques in AD patients brains?
Amyloid beta
How is amyloid-B formed?
By the processing of amyloid precursor protein (APP)
Is amyloid-B only made in the brains of AD patients?
No it's made in the normal brain and secreted.
What does the normal secretion of Beta amyloid prevent?
Formation of aggregates
How many isoforms of the APP are there? How are they different?
3 - differ in terms of the presence or absence of the KPI domain
What is the KPI domain?
A protease inhibitor domain that inhibits the protease function of the APP product.
What is the function of the KPI domain in AD?
It's controversial
What are the 2 pathways by which the APP protein is normally processed?
1. Alpha secretase
2. Beta-secretase
What does the alpha secretase pathway do?
Cleaves right in the middle of the beta-amyloid peptide and prevents the formation of product. A good thing.
What is the product of the Beta secretase pathway?
A product that contains the intact A-beta protein, bound to a stub.
What cleaves the Amyloid-beta protein from the Abeta-Stub precursor?
Gamma secretase
What are the 2 forms in which Amyloid-B can be found in the end?
-40 AA long
-42 AA long
Which form of Amyloid-beta is most amyloidogenic?
42-AA long Amyloid beta
How do the mutations in alzheimer's disease cause amyloid-B plaques?
They increase the ratio of 42:40 AA long product.
Is Alzheimer's disease the only disease where you see Amyloid beta plaques?
No - symptoms of AD are also present in most older patients with DOWNS syndrome
What is the gene defect that causes Downs syndrome?
Trisomy on Ch' 21
What else is on Ch' 21?
APP gene
So what does that make us think causes the dementia in AD?
Overexpression due to the extra gene of APP.
What is Hereditary Cerebral Hemorrhage with Amyloidosis - Dutch type?
A disease of recurrent hemorrhages caused by amyloid-B deposits in blood vessels.
Is there dementia in HCH w/ Amyloidosis Dutch type?
Only when the disease is VASCULAR in origin
How is HCH w/ amyloidosis different from alzheimer's disease?
It is due to an AA substitution in the B-amyloid region of APP, not due to an increased ratio of the 42AA:40AA form.
So AD is caused by a mutation that affects ______ and HCH w/ amyloidosis is caused by a mutation that causes ______:
AD = Processing

HCH = Sticky fibril formation
How many alleles of the amyloid precursor protein do most people have?
2 (i hope so dear me)
How many alleles do people with down syndrome have?
3 - trisomy 21
What happens to one of the two Amyloid precursor protein alleles in patients with familial Alheimer's disease?
It gets a missense mutation - an AA substitution.
What do we know happens to the patients with INHERITED familial alzheimer's disease?
The NORMAL gene undergoes a duplication so that now there are 2 genes for APP on one Ch 21, resulting in Gene DOSAGE.
What is the result of 2 copies of APP on the same chromosome?
An increase in 42AA amyloid-B which causes plaque formation.
What percentage of all alzheimer's disease is familial?
1%
What are most cases of AD?
Sporadic
How many different mutations giving rise to AA substitutions in the APP gene have been identified?
About 20
What is the function of the Beta-amyloid protein?
It's completely unknown
How many isoforms of the APP have the KPI domain?
2 out of the 3 isoforms have it
How is the KPI domain created?
By alternative splicing
Why is the 42 AA form of beta amyloid more amyloidogenic?
Because it has 2 more hydrophobic amino acids
What fraction of familial AD is due to mutations in the APP gene?
only 10%!
So what percent of all AD is due to APP mutations?
10% of 1% --> 0.1%
What happens to B-amyloid produced normally?
It is transported to vasculature and cleared via secretion in blood or perivascular fluid.
Why does B-amyloid sometimes deposit in vasculature versus brain parenchymal tissues?
It's not understood
WHAT IS THE AMYLOID CASCADE HYPOTHESIS?
That accumulations in Amyloid B 42-AA form trigger the pathogenic cascade that causes Alzheimer's disease.
What are tangle formation, nerve cell degeneration, and dementia?
All SECONDARY to amyloid Beta accumulation.
What are 3 problems with the Amyloid Cascade Hypothesis?
1. Some FTLD's (frontotemporal lobar dementias) don't have them
2. Can't be recreated in transgenic mice
3. Distribution of plaques doesn't correlate with pattern and severity of dementia
So what gene mutation accounts for 10% of all familial AD?
The Amyloid-B precursor protein
What gene mutation accounts for 90% of familial AD?
Mutations in Presinilin-1
How many presenilin genes are there?
3
What do the presinilin genes encode?
Components of the Atypical Aspartyl Protease complex
What is the Atypical Aspartyl Protease complex responsible for?
the Gamma secretase pathway
What happens when the Presinilin gene is mutated?
Decreased gamma secretase activity
What results from decreased gamma secretase activity?
An increased ratio of 42:40 AA amyloid beta
How does the Presinilin hypothesis relate to the Amyloid cascade hypothesis?
It casts doubt on it because Presinilin mutations are associated with more FTLDs and are not always seen with Amyloid-beta plaques.
So what is the Presinilin hypothesis?
That Presinilin mutations are the trigger for the neurodegeneration in AD and everything else is 2ndary to it
Does inactivating presinilin function in an adult mouse cause dementia and neurodegeneration?
YES - and it completely mimics AD!
Do presinilin mutations inhibit functions that only lead to accumulation of amyloid Beta?
No - they do other things too that lead to degeneration.
What is the major component of NEUROFIBRILLARY TANGLES?
Tau
What about Tau forms these tangles?
When it is hyperphosphorylated
What IS Tau?
A microtubule binding protein important for microtubule assembly and stabilization
How many isoforms of Tau are there? How are they encoded?
6 - encoded by alternative splicing of a single gene.
How many tau isoforms are expressed in the normal brain? In what manner?
All six; in a ratio of 1:1:1;1:1:1
What is the tau expression in an AD brain?
The same; it's just hyperphosphorylated.
What characterizes the distribution of Tau deposits in Picks and ALZHEIMERS disease?
They're ONLY in neurons
Where are Tau deposits in other neurodegenerative diseases?
In neurons AND glia
Is the Tau isoform expression equal in ratio in all diseases?
No; there are diseases with 4-repeat isoforms, and 3-repeat isoforms.
How IS tau the same in all tau-associated neurodegenerative diseases?
It is always hyperphosphorylated
What is thought to be the result of this hyperphosphorylation?
Cellular toxicity
What is the most logical role that Tau mutations have in disease?
Interfering with axonal transport.
How much AD is
-Sporadic
-Familial
Sporadic = 90%
Familial = 10%
What is the only known genetic risk factor for sporadic AD?
Apolipoprotein E4 which modulates amyloid B production
Do plaques and tangles appear in aging people normally?
Yes
Is the appearance of tangles and plaques in AD related?
No; they're independent
What appears first in sporadic AD? What appears first in familial AD?
Sporadic: Tangles appear first
Familial: Plaques appear first if there is an APP mutation