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Amyloid: Abnormal protein (Composition/Structure (single protein can form…
Amyloid: Abnormal protein
Composition/Structure
peptides with beta sheet conformation (cross beta)
fibrillar morphology 7-13 nm in diameter (electron microscopy)
Amyloid fibrils are protein homopolymers that adopt diverse cross-β conformations
Amyloid is among the most stable protein conformations
common features include:
β-strands maintained by steric zippers involving hydrophobic side chains or uncharged polar residues
glutamine ladders along the fibril axis
hydrophobic packing of methyl-bearing and aromatic residues
variability in how β-strands align exists among fibrils formed by different proteins
single protein can form different cross-β structures, termed ‘strains’
Human disease amyloids exhibit strain variation --> disease heterogeneity
forms depend on the sites of deposition
senile plaques in the neuropil (low number of cell bodies, unmyelinated axons)
amyloid plaques in white matter
early stage AB deposits: non-fibrillar
late stage: fibrillar
amyloids are composed of an ordered arrange- ment of many (usually thousands) copies of a peptide or protein
insoluble & heterogenous
Amyloid fibrils are formed by normally soluble proteins, which assemble to form insoluble fibers that are resistant to degradation
The fibrillar assemblies are inherently/permanently stable
X-ray fiber diffraction, electron microscopy, solid state nuclear magnetic resonance (ssNMR)42 and electroparamagnetic resonance to determine the structure
fibrils are long, straight and unbranching
made up of individual subunits named “protoflaments" --> often observed to twist around one another to form the mature fibril
senile plaques
extracellular deposits of amyloid beta peptide
accompanied by disruption of synaptic function, neuronal atrophy of the hippocampus and cerebral cortex, dementia and cognitive impairment
divided into:
diffuse
primitive
typical
compact
diffuse type in molecular layer of cerebellum
typical predominant in Purkinje cell layer
cerebral, motor & visual cortices: typical
association cortices: diffuse/primitive
Typical/classical
3 components:
amyloid: central core (packed mass of amyloid fibrils, surrounded by astroglial and microglial processes) & crown (scattered bundles of amyloid fibrils, glial processes)
swollen neurites (dense bodies)
reactive glia
amyloid angiopathy --> vascular origin of these plaques
deep neocortical layers
Primitive
the same 3 components as typical but smaller amyloid amounts
amyloids as scattered bundles of fibrils
Diffuse
no consistent contents
lack glial reaction and swollen neuritis (at least in the early phases)
Compact
mass of packed amyloid fibrils, similar to central core of typical
burned-out: disappearing stages of typical plaques
Amyloidosis (group of diseases)
abnormal proteins/amyloid fibrils build up
37 human proteins associated with diseases
PrP Prion: infectious amyloid protein
can convert other non-infectious proteins into infectious form
transmissible spongiform encephalopathies eg. Creutzfeldt-Jakob Disease, Fatal Familial Insomnia
create protein-misfolding chain reaction
across different species
Microtubule-associated protein tau--> Taupathies eg. Pick's Disease (frontotemporal lobar degeneration)
intracellular neurofibrillary tangles (NFTs)
alpha synuclein --> PD, Dementia with Lewy Bodies, Multiple System Atrophy
Huntingtin exon 1 HTT --> HD
beta amyloid from amyloid precursor protein --> AD
Transthyretin TTR
transport protein in the serum & CSF
carries thyroid hormone T4
in peripheral nervous system
Familial amyloid polyneuropathy (FAP)
despite the obvious differences in amino acid sequences and native structure, these amyloidogenic peptides all appear to share a common β-sheet conformation of their polypeptide backbone
deposition of amyloid is an early step in AD pathogenesis --> Amyloid Cascade Hypothesis of AD (Hardy & Higgins, 1992)
in AD: Aβ assembles into insoluble amyloid fibrils that accumulate in extracellular neuritic plaques
altered metabolism of amyloid precursor protein (APP) initiates the pathogenesis of AD
plaques would cause further pathological changes including the formation of neurofibrillary tangles and compromised synaptic connections --> neuronal cell loss and dementia
BUT: no correlation between the density of plaques and tangles and the severity of AD --> maybe oligomers are the initiators of AD & fibril formation is the end point of the disease
AB is a normal product of APP processing: Metabolism (production), Catabolism (degradation), Clearance (transport out)
APP cleaved by beta and then gamma secretaries to generate A beta --> prime targets for development of anti-AD drugs
cleavage by gamma secretase is imprecise --> heterogeinty of A beta species
those ending at position 40 (40 amino acids) are most abundant, followed by 42
beta secretase activity is increased in sAD & increases with age in rodents
significant amount of amyloid beta remains undegraded --> our bodies need a good mechanism to transport it across BBB out into periphery
Two major intracellular degradation pathways that may be bolstered therapeutically are autophagy and the ubiquitin-proteasome system (UPS)
Autophagy: cell removes dysfunctional components
stimulating autophagy may reduce amyloid toxicity.
stimulating machinery that delivers misfolded proteins to the proteasome
Increasing proteasomal activity in the early-stage model eliminates toxic oligomers or small fibrils
Proteasomes: protein complexes which degrade unneeded or dysfunctional proteins by proteolysis (breaking peptide bonds)
NON-PATHOGENIC functional extracellular amyloid: normal biological activities eg. naturally abundant in human semen
Beneficial:
pigment formation
long term potentiation LTP
sperm selection
antimicrobial functions: protect sperm cells
peptide hormone release
But might promote HIV infection
Understand differences between functional and pathological amyloids!
protein called Pmel17 is involved in the biosynthesis of melanin --> forms fibrous structures with characteristics of amyloid fibrils
Aβ fibrils implicated in cerebral amyloid angiopathy (CAA): they accumulate in cerebral vasculature, causing hemorrhage, stroke and inflammation
Amyloid Assembly
Some amyloidogenic proteins, such as tau and αSyn, are natively unfolded
steric zippers
pairs of self-complementary β-sheets that are formed by very short peptides
mutations in unfolded domains can introduce potent steric zippers --> accelerate fibrillization
Mutations are not necessary for amyloidogenicity
Any protein can probably form amyloid under specific environmental conditions
unfolding is necessary but not sufficient for amyloidogenesis: many proteins are intrinsically unfolded but do not form amyloid
dissociation of stable, native oligomers into amyloidogenic monomers that rapidly fibrillize
extracellular mass of amyloid fibrils
biophysical definition: an unbranched protein fiber whose repeating substructure consists of b strands that run perpendicular to the fiber axis, forming a cross-b sheet of indefinite length
History
mid 19th century: describe the iodine stained deposits seen in liver at autopsy
deposits were thought to be carbohydrate in nature until their high nitrogen content was later established
specific binding of amyloid to the dye Congo Red --> suggested that amyloid was fibrillar in structure
progress in biochemical and biophysical techniques enabled the isolation of amyloid fibrils from tissues
characteristic cross-β structure was interpreted from X-ray fiber diffraction patterns
mechanisms underlying polymerisation of soluble, monomeric peptide into mature insoluble fibrils may provide researchers with possible therapeutic approaches to halting, reversing or avoiding fibril formation
conversion of soluble peptide to insoluble amyloid often involves the production of a partially unfolded intermediate (thermodynamically unfavorable state)
very early species: dimers, trimers, tetramers (collectively known as oligomers
fibril formation may follow an ‘offset pathway’ without the production of fibrils but instead involving conversion of the intermediates into amorphous deposits
Anti-amyloid drugs
toxic & bad influence on immune system
inflammatory response (meningoencephalitis)
monoclonal antibodies for plaque clearance