Physics Department, College of Science

Misfolding of Proteins to Amyloids and

Alzheimer’s Disease
Amani Alsaeedi, Anfal Aljishi, Bana Anabosi, Khloud Bajamel, Maram Alnakhli
Instructed by: Dr. Noha Saleh

Abstract Amyloid diseases: Alzheimer’s Disease

Mistakes in protein folding can lead to protein conformational diseases that have many different Diseases associated with amyloid fibrils are broadly classified into degenerative diseases (such
etiologies, which includes the aspect of the protein aggregation and deposit of Amyloid- β Fibrils (Aβ), as Alzheimer’s disease) and prion diseases (such as BSE). Prions are an unusual subset of
through different pathways, and that is linked to be the cause of common neurodegenerative amyloids that are known to induce amyloid fibril formation in vivo in other systems. Alzheimer’s
diseases such as Alzheimer’s Disease. This review discusses the unique structure of amyloid fibrils, disease one of the most well-known of all amyloid diseases and is presently the fourth most
the kinetics and formation of the aggregates along, and a few factors that affect the formation of common cause of death in the developed world. Due to the aging of worldwide population,
such species. This review also explores Alzheimer’s Disease as an example of amyloid diseases and Alzheimer’s disease presents a growing social and economic burden to society.The causes and
the various approaches to treat these amyloid fibrils. pathology of the disease itself are still not entirely understood. Electron microscopy of the
plaques from Alzheimer’s disease sufferers in 1963 showed the presence of amyloid fibrils in
Introduction the brains of patients with Alzheimer’s disease,and this highlighted the link between the
amyloid fibrils and the disease. There are two forms of Alzheimer’s disease: an early onset
The folding of proteins has been at the heart of protein chemistry and biophysics ever since the version caused by an autosomal dominant mutation, and a sporadic form of the disease The
pioneering experiments by the labs of Fred Richards and Christian Anfinsen. Protein synthesis is a best known symptoms of Alzheimer’s disease are memory disorders and impairment of
fundamental process that occurs in the ribosome and involves the coding of amino acids sequences to cognitive domains. These symptoms interfere with the affected individual’s daily life. People
form a polypeptide chain. The folding of this polypeptide chain is the key to activating the polypeptide with Alzheimer’s disease tend to have medial temporal lobe atrophy of the brain, as well as
chain to form a normally functioning protein in its native conformation. The classic experiment of hypometabolism and hypoperfusion in the temporoparietal areas of the brain, and these symp-
Anfinsen, had developed what he called his "thermodynamic hypothesis" of protein folding to explain toms can be detected by MRI and PET.
the native conformation of amino acid structures. He theorized that the native or natural conformation
occurs because this particular shape is thermodynamically the most stable in the intracellular
environment. Folding of proteins is assisted by various factors, such as molecular chaperones, ionic
environment, cofactors, and enzymes. Protein misfolding can cause the aggregation of
proteins and the deposit of whats called Amylod
fibrils. Amyloid fibril formation is associated with
number of incurable diseases. The most well-
known amyloid disease is Alzheimer's disease and
it was first described by Alois Alzheimer in 1906.

FIGURE Pathway of protein folding. Normal folding occurs

with the help of chaperones and other factors. Misfolding of
polypeptides can lead to targeting to inappropriate cellular
locations, or to degradation as a part of the quality control
process, or to aggregation. The aggregated product is often Amyloid fibrils in Alzheimer’s disease visualized using gold nanoparticles, Biotechniques
resistant to proteolysis and forms aggregates, such as
amyloid plaques.
Amyloid Disease Therapeutics
Treatment methods focus on replacing the neurotransmitters lost during the onset of Alzheimer's
disease in the brain to help alleviate the symptoms of the disease. Aß is a small protein found in
Amyloid Fibril Kinetics and Formation mammals that is expressed from a gene found on chromosome 21 in humans. cytotoxic intermediates
of Aß fibril formation result in neuronal disruption, which in turn results in the symptoms seen in
Amyloid fibrils form from partially denatured proteins that Alzheimer's disease. In Alzheimer’s disease, Aß amyloid plaques first appear in the basal part of the
were subjected to mildly denaturing conditions. These isocortex and spread to the rest of the isocortex as the disease progresses. In late stage Alzheimer’s
conditions are required for the protein to unfold and re-fold disease, these amyloid plaques can be found thought the brain, with the isocortex having the highest
into an alternative form that is capable of self-assembling into amyloid plaque density. Aß is a very popular model protein to study amyloid fibril formation and
an amyloid fibril. As the amyloid-forming version of the inhibition in vitro. Other approaches to treating Alzheimer’s disease: being investigated, such as
protein is often thermodynamically more stable than the modifying the production of the amyloidogenic protein and targeting Serum Amyloid Protein (SAP).
native state, amyloid fibril formation is usually irreversible in decrease the production of Aß. Hence, drugs that inhibit ß-secretase or g-secretase, or increase the
physiological conditions. Individ-ual monomers of amyloid activity of a-secretase would reduce the amount of Aß and this could possibly halt the progression of
protein (aka amyloid precursors) self-assemble to form Alzhei-mer’s disease. γ-secretase is a difficult protein to target for a therapeutic against Alzheimer’s
oligomers or protofibrils that elongate and intertwine to form disease, due to the involvement of γ-secretase in many other signaling pathways in the cell, Inhibiting
mature amyloid fibrils. These units may even induce other the activity of γ-secretase may result in side effects such as hematological and gastrointestinal
native proteins to turn into more precursors as seen in prion toxicity, skin reactions, and even changes to hair colour. Second- Generation γ-secretase inhibitors
diseases. There are several conditions that are known to trigger or accelerate fibril formation, and that do not affect notch signaling are currently being investigated, and some of these inhibitors show
factors that cause protein denaturation often cause amyloid fibril formation. These include denaturing promising results as a therapeutics. prevention of mitochondrial dysfunction, targeting of tau
temperatures, denaturing pH conditions, various solvents, metal ions such as Zn21 and Cu21 ,and shear proteins, as well as neurotrophins that prevent neuronal cell death. One advantage of this method is
forces/agitation. It is notable, that while some of these factors are not essential to forming amyloid that cholesterol lowering statin drugs are presently widely prescribed, well tolerated, and that
fibrils, they do alter the kinetics of fibril formation. For example, amyloid fibrils can form in the lowering choles- terol levels have some generic health benefits. However, it is still not known how
absence of shear and metal ions. Some factors affect the amount of conversion of protein to amyloid cholesterol affects the production of Aß or the progression of Alzheimer’s disease. Use of natural
fibrils. For instance, increased stirring speed results in an increased conversion of protein into amyloid products to treat amyloid disease: natural product of soy beans, Genistein, is capable of inhibiting
fibrils combined with an increased rate of fibril formation. Amyloid fibrils grown in different conditions amyloid fibril formation of transthyretin. increasing the oral uptake of such products can potentially
also show different levels of cytotoxicity. reduce the effect of amyloid fibril formation in people. A large number of other natural products are
also being investigated as leads in developing drugs to treat Alzheimer’s disease.

Amyloid Fibril Structure

Many different proteins can form amyloid fibrils. Amyloids are highly Conclusion
ordered protein , is composed of the cross-β-sheet entity,which is an
almost indefinitely repeating two-layered intermolecular β-sheet motif. Amyloid fibrils are fibrillar protein aggregates that are self-assembled from β-sheet rich, misfolded
There are several different proposed models for the self-assembly proteins that are associated with several incurable diseases. Many unrelated proteins can form
amyloid fibrils from their mono- mers and they are the refolding model. amyloid fibrils, and it is believed that amyloid fibril formation is a universal property of proteins. The
Three mod- els of conversion from the native protein to an amyloid. self-assembly of these fibrils typically follows three phases: a lag-phase, an elongation phase, and a
Refolding is where a structured native protein unfolds to an plateau phase. Many factors, such as stirring speed, metal ions, temperature and pH, can affect the
intermediate before forming an amyloid fibril. Natively disordered kinetics of formation and the morphology of these fibrils. Amyloid fibrils can affect cells and organs
model occurs when the native protein has little secondary structure in many different detrimental ways, and this is believed to eventually result in various amyloid
and folds into an amyloid, and gain-of-interaction occurs where a diseases. The most well-known amyloid disease is Alzheimer’s disease. There is no cure for
portion of the protein allows for interactions with other protein Alzheimer’s disease at present and treatment of Alzheimer’s disease is largely limited to symptom
molecules to form the amyloid fibril. Amyloid fibrils formed by the management. Several different approaches to treating amyloid diseases are being investigated such
gain-of-interaction model retain a significant amount of native protein as amyloid fibril inhibitors and regulating the production of Aβ. Although many of these drugs are in
structure. clinical trials, to date there has yet been a therapeutic developed to combat these amyloid diseases.

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