Lecture 20 Flashcards
Alzheimer's Disease part 1
First doccumeneted case of AD was in…
1906
____ MILLIONS PATEINTA ARE ESTIMATED TO HAVE ad
35.6
__ million patients by 2050
114 million
Gross Atrophy (shrinage) of the brain is characters but not _____ to AD
specific
True or False Extracellular Neuritic (amylooid) plaques are specific to AD
True
Other general Neuropathology of AD:
Intraneuraonal ______ tangles
Cerebrovascular ______ (CAA)
Activation of ____ , hypertrophy of _________
Degree of dementia/memory impairment - loss of _______
Loss of _________as disease progresses
Intraneuraonal Neurofibrillary tangles
Cerebrovascular Amyloid
Activation of microglia, hypertrophy of astrocytes
Degree of dementia/memory impairment - loss of synapses (correlated)
Loss of neurons as disease progresses
When stained Amyloid plaques appear..
dark and circular - throughout the grey matter
Amyloid plaques:
Aggregated amyloid beta _-____ (forming fibrils)
______ -___birefringence with congo red stain
many _________ beta components in plaques
High concentration of _____ions
Readily ____ ___ in brain
May be “end point” of _____pathway
Assoc. with ________ inflammation
Aggregated amyloid beta peptide (forming fibrils)
Green-red birefringence with congo red stain
many non-amyloid beta components in plaques
- a “sink”, very sticky
High concentrationof metal ions
Readily turned over in brain
May be “end point” of amyloid pathway
Assoc. with secondary inflammation
What is amyloid?
Starch-like material
Rich beta-sheet protein structure
Can have fibrils in it
How is Amyloid formed?
Not specific for a primary protein sequences
(Amyloid can form from other proteins in different tissues)
- Proteins begin as unstructured monomers (little helix and sheet structure)
- with Inc. concentration or under certain envirnomental conditions, B-she1et structure increases
- Monomers begin to form parallel B-Sheet structures (protofibril_
protofibrils mature into fibrils and form plaques
Monomeric AB peptide can aggregate to form fibrillar _______
Monomeric AB peptide can aggregate to form fibrillar amyloid
Monomeric AB can form oligomeric (a molecular complex that consists of a few monomer units) species - consisting of 2-10+ monomers packed closely together
Oligomers may become cross-linked by specific amino-acid modificaions - what does this do for the oligomer?
Increases stability
Oligomers are thought to be the primary ___ form of AB
toxic
How is amyloid beta peptide produced?
- Cleavage of larger amyloid Precursor protein (APP) by ‘secretases’ (proteases) at the membrane of grey matter in the brain
- Amyloid beta (AB) is released into the ECS (can be recycled)
- Amyloid deposits form between cells
Specifically the cleavage is performed by what?
beta secretase and then gamma secretase
true or False
APP can also be cleaved by a-secretase at a different site which prevents AB from forming
true
The remaining APP can be released as soluble APP
AB peptide is cut from a part of the APP inside or outside the cell?
outside the cell
which enzyme intially cuts APP?
BACE 1
APP is an integral membrane protein concentrated at _______ in the brain
synapses
Gene for APP is located on chromosome __
21
APP is complex, it have complex processing, what are some activities is has been described as having a part in?
Growth Promotion
reglation of synaptic function
metal homeostasis
Cell signalling
Which enzymes in the brain can degrade the amyloid peptide?
Insulin degrading enzyme
Neprilysin
Matrix metalloprotreases
Angiotensin converting enzymes
Reduction in ______activity has been observed in AD brain
Reduction in protease activity has been observed in AD brain
______can also remove amyloid, especially aggregated peptide and plaques
Microglia can also remove amyloid, especially aggregated peptide and plaques
What are the two different processes of getting rid of Amyloid in the brain?
- Degraded by proteases leading to clearance:
Insulin degrading enzyme
Neprilysin
Matrix metalloprotreases
Angiotensin converting enzymes
- Removed by Microglia
the normal monomeric form of Amyloid can have an ______ fucntion
antioxidant
Can also moduate metals in the brain
What are the abnromal fucntions of Amyloid?
Aggregation into amyloid
Aggregation in oligomers
Neurotoxic effects
inflammation
Other than Amyloid what is the other neuropathologic elements in AD?
Neurofibrillary triangles (NT)
NTs are formed from what?
Tangles, composed of a hyperphosphorylated form of microtubule protein called tau
the hypophosphorylation causes tau to become ______ and aggregated into ____ (filaments of protein twisted together in pairs)
the hypophosphorylation causes tau to become insoluble and aggregated into NFTs
Neurofibrillary tangles are also associated with _____
tauopathies (frontotemporal dementia)
What does tau do under normal conditions?
tau is normally attaches to microtubules and allows struture movement and intracellular transport
What triggers tau to be released from microtubules
hyperphosphorylation,
results in abnormal cytoskeletal structure and inhibition of IC transport
What increases when tau is released from microtubules and what does this cause
INcreased oxidative stress in the neurons - causes cross-linking that further inhibits the degradation of NFTs by the cell
Literature suggests Amyloid beta comes before…
tau hyperphosphorylation
What are the contributing factors to AD?
Age
Oxidative stress
loss of normal neuronal metal homeostasis
inflammation
‘leakage’ of moleclar intermediates from the mitochondrial electron transport chain can lead to
oxidative and nitrosative stress
imbalance between generation and removal of radicals
Peroxynitrite and Hydroxyl radical are..
very dangerous compounds, will bind to things and irreversibly change it leading to oxidative damage
What are some sources of oxygen radicals in AD?
Mitochondria
Brain has high oxygen consumption and low antioxidant levels
Non-dividing cells build up oxidatively damaged molecules
amyloid beta can induce radicals
metals
inflammation
Metals can _____ free radicals
Metals can catalyse free radicals
Consquences of excessive oxygen radicals?
protein oxidation
DNA oxidation and strand breaks
Downstream effects include:
Nerotoxic actions of latered lipids
aggregated protein
DNA damage
Biometals are?
copper, zinc, iron - ones with important enzymatic functions and so on…
High levels of copper and zinc are found in..
AD plaques
There is strong evidence of altered zinc and copper _______ in AD brain
metabolism
There are high levels of copper and zinc in AD brain ___
extracellular fluid
There can be up to a 50% decrease in ______ of affected regions in AD
neurons
metals are the main source of ___ ______ generation in the brain
free radical
Amyloid beta binds copper and zinc at several sites involving _____ and _______ AAs
Histidine and Tyrosine
Binding of metals by AB…
promotes the aggregation of the peptide
copper induces formation of neurotoxic oligomers
Copper causes ____-_____ between AB monomers to form stable neurotoxic dimers
cross-linking
Amyloid deposits large amoutns of ____ and ___
copper and zinc
AB has binding sites for ____ and _____
copper and zinc
What are the sources of imflammation in AD?
Resting resident brain macrophaages (microglia) become activated
infiltration of peripheral monocytes
What initiated inflammation in AD?
likley response to aggregated zmyloid
response to degenerating synapses and neurons
What are the consquences of inflammation in AD?
release of neurotoxic cytokines
Increased free radical production
Further damage to neurons and synapses
Summary of AD characteristics?
loss of memory and higher brain function
Brain atophy
EC amyloid plaques
IC nerofibrillary triangles
Gliosis (activation of microglia)
Amyloid plaques are composed of…
Amyloid beta peptide
Amyloid is ___ under nromal light and ____/____ under polarised light when stain Congo red
Amyloid is redunder nromal light and Green/yellow under polarised light when stained Congo red
