Amyloid beta
Encyclopedia
Amyloid beta is a peptide
of 36–43 amino acid
s that is processed from the Amyloid precursor protein
. While it is most commonly known in association with Alzheimer's disease
, it does not exist specifically to cause disease. Evidence has been found that Aβ has multiple non-disease activities.
enzymes, protection against oxidative stress
regulation of cholesterol
transport functioning as a transcription factor
, and anti-microbial activity (potentially associated with Aβ's pro-inflammatory activity).
plaques (deposits found in the brain
s of patients with Alzheimer's disease). Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis
(a muscle disease), while Aβ can also form the aggregates that coat cerebral blood vessels in cerebral amyloid angiopathy. The plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers, a protein fold
shared by other peptides such as the prion
s associated with protein misfolding diseases. Recent research suggests that soluble oligomeric forms of the peptide may be causative agents in the development of Alzheimer's disease.
(APP), a transmembrane
glycoprotein
of undetermined function. APP can be processed by α-
, β-
and γ-secretase
s; Aβ protein is generated by successive action of the β and γ secretases. The γ secretase, which produces the C-terminal end of the Aβ peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 36-43 amino acid
residues in length. The most common isoforms are Aβ40 and Aβ42; the shorter form is typically produced by cleavage that occurs in the endoplasmic reticulum
, while the longer form is produced by cleavage in the trans-Golgi
network. The Aβ40 form is the more common of the two, but Aβ42 is the more fibrillogenic and is thus associated with disease states. Mutations in APP associated with early-onset Alzheimer's have been noted to increase the relative production of Aβ42, and thus one suggested avenue of Alzheimer's therapy involves modulating the activity of β and γ secretases to produce mainly Aβ40.
processing. Increases in either total Aβ levels or the relative concentration of both Aβ40 and Aβ42 (where the former is more concentrated in cerebrovascular plaques and the latter in neuritic
plaques) have been implicated in the pathogenesis
of both familial and sporadic Alzheimer's disease. Due to its more hydrophobic nature, the Aβ42 is the most amyloidogenic form of the peptide. However the central sequence KLVFFAAE is known to form amyloid on its own, and probably forms the core of the fibril.
The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is by no means conclusively established. Intra-cellular deposits of tau protein
are also seen in the disease, and may also be implicated. The oligomers that form on the amyloid pathway, rather than the mature fibrils, may be the cytotoxic species.
An alternative hypothesis is that amyloid oligomer
s rather than plaques are responsible for the disease. Mice that are genetically engineered to express oligomers but not plaques (APPE693Q) develop the disease. Furthermore mice that are in addition engineered to convert oligomers into plaques (APPE693Q X PS1
ΔE9), are no more impaired than the oligomer only mice.
but rather populates a set of structures. As such it cannot be crystallized and most structural knowledge on amyloid beta comes from NMR
and molecular dynamics
. NMR-derived models of a 26-aminoacid polypeptide from amyloid beta (Aβ 10-35) show a collapsed coil
structure devoid of significant secondary structure
content. Replica exchange molecular dynamics studies suggested that amyloid beta can indeed populate multiple discrete structural states; more recent studies identified a multiplicity of discrete conformational clusters by statistical analysis. By NMR-guided simulations, amyloid beta 1-40 and amyloid beta 1-42 also seem to feature highly different conformational states, with the C-terminus of amyloid beta 1-42 being more structured than that of the 1-40 fragment.
Structural information on the oligomeric state of amyloid beta is still sparse as of 2010. Low-temperature and low-salt conditions allowed to isolate pentameric disc-shaped oligomers devoid of beta structure. In contrast, soluble oligomers prepared in the presence of detergents seem to feature substantial beta sheet content with mixed parallel and antiparallel character, different from fibrils; computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers.
There is some indication that supplementation of the hormone melatonin
may be effective against amyloid. Melatonin interacts with amyloid beta and inhibits its agregation This anti-aggregatory activity occurs only through an interaction with dimers of the soluble amyloid beta peptide. Melatonin does not reverse fibril formation or oligomers of amyloid beta once they are formed. This is supported by experiments in transgenic mice which suggest that melatonin has the potential to prevent amyloid deposition if administered early in life, but it may not be efficacious to revert amyloid deposition or treat Alzheimer's disease.
This connection with melatonin, which regulates sleep, is strengthened by the recent research showing that the wakefulness inducing hormone orexin
influences amyloid beta (see below).. Interestingly, animal experiments show that melatonin may also correct mild elevations of cholesterol which is also an early risk factor for amyloid formation.
The cannabinoid HU-210
has been shown to prevent amyloid beta-promoted inflammation.
, rising when an animal (mouse) or person is awake and falling during sleep. The wakefulness-promoting neuroprotein orexin
was shown to be necessary for the circadian rhythm of amyloid beta production. The report suggested that excessive periods of wakefulness (i.e. due to sleep debt
) could cause chronic build-up of amyloid beta, which could hypothetically lead to Alzheimer's disease
. This is consistent with recent findings that chronic sleep deprivation is associated with early onset Alzheimer's disease.
Melatonin
is also involved in circadian rhythm maintenance. Notably, melatonin
has been connected with the "sundowning" phenomenon, in which Alzheimer's disease patients that have amyloid plaques in the hypothalamus exhibit exacerbation of Alzheimer's disease symptoms late in the day. This "sundowning" phenomenon could be directly or indirectly related to the recently discovered continuous increase in amyloid beta throughout the day.
and vascular.
One highly sensitive method is ELISA
which is an immunosorbent assay which utilizes a pair of antibodies that recognize Amyloid beta.
Imaging compounds, notably Pittsburgh Compound-B, (BTA-1, a thioflavin
), can selectively bind to amyloid beta in vitro and in vivo. This technique, combined with PET
imaging, has been used to image areas of plaque deposits in Alzheimer's patients.
Atomic force microscopy
, which can visualize nanoscale molecular surfaces, can be used to determine the aggregation state of Amyloid beta in vitro.
Dual polarisation interferometry
is an optical technique which can measure the very earliest stages of aggregration and inhibition by measuring the molecular size and densities as the fibrils elongate. These aggregate processes can also be studied on lipid bilayer constructs.
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
of 36–43 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s that is processed from the Amyloid precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
. While it is most commonly known in association with Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, it does not exist specifically to cause disease. Evidence has been found that Aβ has multiple non-disease activities.
Normal Activity of Aβ
Several potential activities have been discovered for Aβ that are not associated with disease, including activation of kinaseKinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
enzymes, protection against oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
regulation of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
transport functioning as a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
, and anti-microbial activity (potentially associated with Aβ's pro-inflammatory activity).
Disease Associations
Aβ is the main component of amyloidAmyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
plaques (deposits found in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
s of patients with Alzheimer's disease). Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis
Inclusion body myositis
Inclusion body myositis is an inflammatory muscle disease, characterized by slowly progressive weakness and wasting of both distal and proximal muscles, most apparent in the muscles of the arms and legs...
(a muscle disease), while Aβ can also form the aggregates that coat cerebral blood vessels in cerebral amyloid angiopathy. The plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers, a protein fold
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
shared by other peptides such as the prion
Prion
A prion is an infectious agent composed of protein in a misfolded form. This is in contrast to all other known infectious agents which must contain nucleic acids . The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection...
s associated with protein misfolding diseases. Recent research suggests that soluble oligomeric forms of the peptide may be causative agents in the development of Alzheimer's disease.
Formation
Aβ is formed after sequential cleavage of the amyloid precursor proteinAmyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
(APP), a transmembrane
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
of undetermined function. APP can be processed by α-
Alpha secretase
Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer's disease-associated peptide amyloid beta when APP is instead processed by beta...
, β-
Bace
Bace is a village in the municipality of Prokuplje, Serbia. According to the 2002 census, the village has a population of 284 people.-References:...
and γ-secretase
Gamma secretase
Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases...
s; Aβ protein is generated by successive action of the β and γ secretases. The γ secretase, which produces the C-terminal end of the Aβ peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 36-43 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues in length. The most common isoforms are Aβ40 and Aβ42; the shorter form is typically produced by cleavage that occurs in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
, while the longer form is produced by cleavage in the trans-Golgi
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
network. The Aβ40 form is the more common of the two, but Aβ42 is the more fibrillogenic and is thus associated with disease states. Mutations in APP associated with early-onset Alzheimer's have been noted to increase the relative production of Aβ42, and thus one suggested avenue of Alzheimer's therapy involves modulating the activity of β and γ secretases to produce mainly Aβ40.
Genetics
Autosomal-dominant mutations in APP cause hereditary early-onset Alzheimer's disease (familial AD). This form of AD only accounts for no more than 10% of all cases, and the vast majority of AD is not accompanied by such mutations. However, familial Alzheimer disease is likely to result from altered proteolyticProteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
processing. Increases in either total Aβ levels or the relative concentration of both Aβ40 and Aβ42 (where the former is more concentrated in cerebrovascular plaques and the latter in neuritic
Neurite
A neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
plaques) have been implicated in the pathogenesis
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
of both familial and sporadic Alzheimer's disease. Due to its more hydrophobic nature, the Aβ42 is the most amyloidogenic form of the peptide. However the central sequence KLVFFAAE is known to form amyloid on its own, and probably forms the core of the fibril.
The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is by no means conclusively established. Intra-cellular deposits of tau protein
Tau protein
Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...
are also seen in the disease, and may also be implicated. The oligomers that form on the amyloid pathway, rather than the mature fibrils, may be the cytotoxic species.
An alternative hypothesis is that amyloid oligomer
Oligomer
In chemistry, an oligomer is a molecule that consists of a few monomer units , in contrast to a polymer that, at least in principle, consists of an unlimited number of monomers. Dimers, trimers, and tetramers are oligomers. Many oils are oligomeric, such as liquid paraffin...
s rather than plaques are responsible for the disease. Mice that are genetically engineered to express oligomers but not plaques (APPE693Q) develop the disease. Furthermore mice that are in addition engineered to convert oligomers into plaques (APPE693Q X PS1
PSEN1
Presenilin-1 is a protein that in humans is encoded by the PSEN1 gene.- Function :Alzheimer's disease patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein...
ΔE9), are no more impaired than the oligomer only mice.
Structure
Amyloid beta is intrinsically unstructured, meaning that in solution it does not acquire a compact tertiary foldProtein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
but rather populates a set of structures. As such it cannot be crystallized and most structural knowledge on amyloid beta comes from NMR
NMR
NMR may refer to:Applications of Nuclear Magnetic Resonance:* Nuclear magnetic resonance* NMR spectroscopy* Solid-state nuclear magnetic resonance* Protein nuclear magnetic resonance spectroscopy* Proton NMR* Carbon-13 NMR...
and molecular dynamics
Molecular dynamics
Molecular dynamics is a computer simulation of physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a period of time, giving a view of the motion of the atoms...
. NMR-derived models of a 26-aminoacid polypeptide from amyloid beta (Aβ 10-35) show a collapsed coil
Random coil
A random coil is a polymer conformation where the monomer subunits are oriented randomly while still being bonded to adjacent units. It is not one specific shape, but a statistical distribution of shapes for all the chains in a population of macromolecules...
structure devoid of significant secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
content. Replica exchange molecular dynamics studies suggested that amyloid beta can indeed populate multiple discrete structural states; more recent studies identified a multiplicity of discrete conformational clusters by statistical analysis. By NMR-guided simulations, amyloid beta 1-40 and amyloid beta 1-42 also seem to feature highly different conformational states, with the C-terminus of amyloid beta 1-42 being more structured than that of the 1-40 fragment.
Structural information on the oligomeric state of amyloid beta is still sparse as of 2010. Low-temperature and low-salt conditions allowed to isolate pentameric disc-shaped oligomers devoid of beta structure. In contrast, soluble oligomers prepared in the presence of detergents seem to feature substantial beta sheet content with mixed parallel and antiparallel character, different from fibrils; computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers.
Intervention strategies
Researchers in Alzheimer's disease have identified five strategies as possible interventions against amyloid:- β-SecretaseBaceBace is a village in the municipality of Prokuplje, Serbia. According to the 2002 census, the village has a population of 284 people.-References:...
inhibitorEnzyme inhibitorAn enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
s. These work to block the first cleavage of APP outside of the cell. - γ-Secretase inhibitors (e. g. semagacestatSemagacestatSemagacestat was a candidate drug for a causal therapy against Alzheimer's disease. It was originally developed by Eli Lilly and Élan, and clinical trials were conducted by Eli Lilly...
). These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of Aβ and its toxic fragments. - Selective Aβ42 lowering agents (e. g. tarenflurbil). These modulate γ-secretase to reduce Aβ42 production in favor of other (shorter) Aβ versions.
- Immunotherapies. These stimulate the host immune system to recognize and attack Aβ or provide antibodies that either prevent plaque deposition or enhance clearance of plaques.
- Anti-aggregation agents such as apomorphineApomorphineApomorphine is a non-selective dopamine agonist which activates both D1-like and D2-like receptors, with some preference for the latter subtypes. It is historically a morphine decomposition product by boiling with concentrated acid, hence the -morphine suffix...
. These prevent Aβ fragments from aggregating or clear aggregates once they are formed.
There is some indication that supplementation of the hormone melatonin
Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
may be effective against amyloid. Melatonin interacts with amyloid beta and inhibits its agregation This anti-aggregatory activity occurs only through an interaction with dimers of the soluble amyloid beta peptide. Melatonin does not reverse fibril formation or oligomers of amyloid beta once they are formed. This is supported by experiments in transgenic mice which suggest that melatonin has the potential to prevent amyloid deposition if administered early in life, but it may not be efficacious to revert amyloid deposition or treat Alzheimer's disease.
This connection with melatonin, which regulates sleep, is strengthened by the recent research showing that the wakefulness inducing hormone orexin
Orexin
Orexins, also called hypocretins, are the common names given to a pair of excitatory neuropeptide hormones that were simultaneously discovered by two groups of researchers in rat brains....
influences amyloid beta (see below).. Interestingly, animal experiments show that melatonin may also correct mild elevations of cholesterol which is also an early risk factor for amyloid formation.
The cannabinoid HU-210
HU-210
HU-210 is a synthetic cannabinoid that was first synthesized in 1988 from -Myrtenol by the group led by Professor Raphael Mechoulam at the Hebrew University. HU-210 is 100 to 800 times more potent than natural THC from cannabis and has an extended duration of action...
has been shown to prevent amyloid beta-promoted inflammation.
Circadian rhythm of amyloid beta
A 2009 report has just shown that amyloid beta production follows a circadian rhythmCircadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
, rising when an animal (mouse) or person is awake and falling during sleep. The wakefulness-promoting neuroprotein orexin
Orexin
Orexins, also called hypocretins, are the common names given to a pair of excitatory neuropeptide hormones that were simultaneously discovered by two groups of researchers in rat brains....
was shown to be necessary for the circadian rhythm of amyloid beta production. The report suggested that excessive periods of wakefulness (i.e. due to sleep debt
Sleep debt
Sleep debt or sleep deficit is the cumulative effect of not getting enough sleep. A large sleep debt may lead to mental and/or physical fatigue....
) could cause chronic build-up of amyloid beta, which could hypothetically lead to Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. This is consistent with recent findings that chronic sleep deprivation is associated with early onset Alzheimer's disease.
Melatonin
Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
is also involved in circadian rhythm maintenance. Notably, melatonin
Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
has been connected with the "sundowning" phenomenon, in which Alzheimer's disease patients that have amyloid plaques in the hypothalamus exhibit exacerbation of Alzheimer's disease symptoms late in the day. This "sundowning" phenomenon could be directly or indirectly related to the recently discovered continuous increase in amyloid beta throughout the day.
Measuring amyloid beta
There are many different ways to measure Amyloid beta. It can be measured semi-quantitatively with immunostaining, which also allows one to determine location. Amyloid beta may be primarily vascular, as in cerebral amyloid angiopathy, or in senile plaquesSenile plaques
Senile plaques are extracellular deposits of amyloid in the gray matter of the brain. The deposits are associated with degenerative neural structures and an abundance of microglia and astrocytes...
and vascular.
One highly sensitive method is ELISA
ELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...
which is an immunosorbent assay which utilizes a pair of antibodies that recognize Amyloid beta.
Imaging compounds, notably Pittsburgh Compound-B, (BTA-1, a thioflavin
Thioflavin
Thioflavin can refer to either of two dyes used for histology staining and biophysical studies of protein aggregation.Thioflavin T is a benzothiazole salt obtained by the methylation of dehydrothiotoluidine with methanol in the presence of hydrochloric acid...
), can selectively bind to amyloid beta in vitro and in vivo. This technique, combined with PET
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
imaging, has been used to image areas of plaque deposits in Alzheimer's patients.
Atomic force microscopy
Atomic force microscope
Atomic force microscopy or scanning force microscopy is a very high-resolution type of scanning probe microscopy, with demonstrated resolution on the order of fractions of a nanometer, more than 1000 times better than the optical diffraction limit...
, which can visualize nanoscale molecular surfaces, can be used to determine the aggregation state of Amyloid beta in vitro.
Dual polarisation interferometry
Dual Polarisation Interferometry
Dual polarization interferometry is an analytical technique that can probe molecular scale layers adsorbed to the surface of a waveguide by using the evanescent wave of a laser beam confined to the waveguide...
is an optical technique which can measure the very earliest stages of aggregration and inhibition by measuring the molecular size and densities as the fibrils elongate. These aggregate processes can also be studied on lipid bilayer constructs.