Amyloid and tau are proteins found in the brain that play complex roles in its health. While beneficial under normal conditions, their abnormal behavior is linked to significant neurodegenerative conditions. Understanding their healthy functions and pathological transformations is crucial for comprehending brain diseases.
The Normal Functions of Amyloid and Tau
Amyloid beta (Aβ) peptides are fragments derived from a larger protein called amyloid-beta precursor protein (APP), which is found on cell membranes. While the full scope of Aβ’s normal function is still being investigated, low levels of Aβ are thought to contribute to maintaining normal brain function. Aβ is involved in regulating synaptic function, promoting neuronal growth and survival, protecting against oxidative stress, and may play a role in antimicrobial defense.
Tau proteins are abundant in neurons, particularly in the central nervous system, and are primarily found in axons. Their main function is to stabilize microtubules, internal tracks within neurons. Microtubules are essential for maintaining the neuron’s structure and facilitating the transport of nutrients, organelles, and other molecules throughout the cell. Tau binds to microtubules through specific domains, promoting their assembly and stability. This support for axonal transport and neuronal structure is important for proper brain function.
The Pathological Transformation of Amyloid and Tau
The transformation of amyloid-beta to a harmful state involves aggregation. Amyloid-beta peptides are produced when APP is cleaved by enzymes called beta-secretase and gamma-secretase. These Aβ molecules can then aggregate, initially forming soluble oligomers, which are small clumps of a few molecules. These oligomers can act as “seeds” that induce other Aβ molecules to misfold and join the aggregates, leading to a chain reaction.
This aggregation culminates in the formation of amyloid plaques. These dense, insoluble deposits are found outside neurons in the extracellular space. Plaques are primarily composed of beta-amyloid peptides and are believed to disrupt communication between neurons, leading to inflammation and neuronal damage. The exact mechanisms by which these plaques cause harm are still under investigation, but they are thought to contribute to neuronal dysfunction and death.
Tau protein undergoes a pathological transformation, becoming hyperphosphorylated, meaning it accumulates an excessive number of phosphate groups. This hyperphosphorylation causes tau to detach from microtubules, compromising their stability. Once detached, these abnormally phosphorylated tau proteins aggregate into insoluble threads that twist together to form neurofibrillary tangles. These tangles are found inside neurons, distinguishing them from extracellular amyloid plaques. The formation of these intracellular tangles disrupts the internal transport system of neurons, hindering the movement of essential molecules and contributing to neuronal dysfunction and cell death.
Amyloid and Tau in Neurodegenerative Diseases
The abnormal accumulation of amyloid and tau proteins is a defining feature of several neurodegenerative diseases. Alzheimer’s disease (AD) is the most common condition associated with both amyloid plaques and neurofibrillary tangles. The “amyloid cascade hypothesis” posits that amyloid-beta peptide accumulation in the brain is an early and central event. This event triggers subsequent pathological changes, including tau tangle formation, and leads to neuronal dysfunction.
As Alzheimer’s disease progresses, tau protein begins to form tangles, which bind to the internal structure of neurons and block their communication. While both plaques and tangles are present in AD, their specific contributions and temporal appearance can vary. For instance, some research suggests that amyloid build-up can cause tau to spread rapidly in the brain. In addition to AD, tau pathology is a prominent feature in a group of disorders called tauopathies, where tau protein deposition is the primary characteristic.
Examples of tauopathies include Frontotemporal Dementia (FTD), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and Chronic Traumatic Encephalopathy (CTE). While Alzheimer’s disease is sometimes considered a secondary tauopathy due to co-occurring amyloid pathology, primary tauopathies are defined by tau aggregates as the sole molecular lesion. Another condition involving amyloid is cerebral amyloid angiopathy (CAA), where amyloid proteins build up in the brain’s blood vessels, making them leaky and leading to bleeding inside the brain. CAA is a common cause of cognitive decline.
Current Approaches to Detection and Treatment
Detecting amyloid and tau pathology in living individuals has advanced. Advanced imaging techniques, particularly Positron Emission Tomography (PET) scans, visualize amyloid plaques and neurofibrillary tangles in the brain. Several amyloid PET tracers are approved for clinical use, and new tau PET tracers are emerging with improved specificity for detecting tau tangles in AD. These scans aid in early and differential diagnosis of AD and can monitor disease progression.
Biomarker analysis in cerebrospinal fluid (CSF) and blood tests also offer insights into amyloid and tau pathology. CSF tests measure levels of Aβ42, total tau, and phosphorylated tau (p-tau) proteins. Decreased Aβ42 levels in CSF mark amyloid deposition in the brain, while elevated total tau and p-tau levels indicate neurodegeneration and tauopathy. These CSF markers aid in diagnosis, differentiate AD from other conditions, and predict disease progression.
Blood-based biomarkers are a rapidly developing area, offering less invasive alternatives to PET scans and lumbar punctures. These tests measure abnormal forms of tau, such as pTau181 and pTau217, and amyloid-beta proteins in the bloodstream. Advances in assay sensitivity allow detection of these proteins at very low concentrations, potentially detecting disease signs many years before symptoms appear.
Current therapeutic strategies target amyloid and tau pathology. For amyloid, approaches include immunotherapies using monoclonal antibodies like lecanemab (Leqembi) and donanemab (Kisunla). These are designed to reduce beta-amyloid in the brain and slow cognitive decline in people with early Alzheimer’s. These treatments work by preventing plaque deposition or enhancing their clearance.
Targeting tau pathology is also a focus, as tau accumulation correlates with symptom severity. Strategies include inhibiting tau aggregation, stabilizing microtubules, and active or passive immunotherapies designed to clear tau. While many early attempts targeting tau were discontinued due to toxicity or lack of efficacy, most tau-targeting agents in clinical trials are now immunotherapies, showing promise in preclinical studies. Developing effective treatments remains challenging, highlighting the need for continued research and early detection efforts.