Amyloid fibrils are abnormal, insoluble protein aggregates that form in the body. These fibrous structures are composed of proteins that have lost their usual shape. While associated with disease, some functional amyloid fibrils exist in nature, playing roles in bacterial biofilms or fungal structures. Their presence in human tissues indicates various health conditions.
The Building Blocks: Protein Misfolding
Proteins normally fold into specific three-dimensional shapes that allow them to perform their biological functions. Under certain conditions, a protein can lose its correct structure, a process known as misfolding. This misfolding can expose regions of the protein that are usually hidden, making them prone to sticking to other similarly misfolded proteins.
Misfolded proteins aggregate, forming clumps that grow into larger, highly organized structures called amyloid fibrils. These fibrils have a “cross-beta sheet” structure, where individual protein strands align perpendicular to the fibril’s long axis, held together by hydrogen bonds. This arrangement results in a stable, insoluble aggregate resistant to the body’s normal protein degradation processes.
Diseases Linked to Amyloid Fibrils
The accumulation of amyloid fibrils is associated with a range of human diseases, often referred to as amyloidoses. In Alzheimer’s disease, for instance, two specific proteins are implicated: beta-amyloid (Aβ) forms extracellular plaques in the brain, while tau protein forms intracellular tangles. These distinct protein aggregates contribute to the cognitive decline observed in the disease.
Parkinson’s disease involves alpha-synuclein protein aggregating into amyloid fibrils, found in Lewy bodies within brain cells. Systemic amyloidoses affect various organs throughout the body, not just the brain. Examples include transthyretin amyloidosis (ATTR), where misfolded transthyretin can deposit in the heart or peripheral nerves, and light chain amyloidosis (AL), caused by misfolded immunoglobulin light chains, often impacting kidneys or the heart.
How Amyloid Fibrils Cause Harm
Amyloid fibrils contribute to cellular dysfunction and disease progression through several mechanisms. One way is direct cellular toxicity, where these aggregates can disrupt cell membranes, leading to ion leakage and cell death. This membrane damage can be caused by the fibrils themselves or by smaller intermediate aggregates formed during their assembly.
Fibril accumulation promotes oxidative stress, increasing reactive oxygen species that damage cells and tissues. Inflammation is another consequence, as amyloid deposits can activate the immune system, leading to further tissue damage. Amyloid fibrils can also interfere with normal cellular processes, such as protein transport, potentially leading to toxic substance buildup inside cells.
Detection and Research Directions
Detecting amyloid fibrils involves various methods depending on the affected area. For brain-related conditions like Alzheimer’s disease, Positron Emission Tomography (PET) scans using specific tracers can visualize amyloid-beta plaques. In systemic amyloidoses, biopsies of affected tissues are often used to confirm amyloid deposits. Researchers are also investigating biomarkers in bodily fluids, such as cerebrospinal fluid or blood, for less invasive diagnostic approaches.
Research focuses on developing new therapeutic strategies to combat amyloid-related diseases. These strategies include designing drugs that prevent proteins from misfolding and forming fibrils, or therapies aimed at clearing existing amyloid deposits from tissues. Other approaches explore mitigating the toxic effects of the fibrils on cells, even if they cannot be fully removed. Developing effective treatments faces challenges due to the complex nature of fibril formation and their diverse impacts on the body.