The brain is an intricate organ that supports thought, memory, and movement. As people age, two specific protein accumulations, known as plaques and tangles, are studied for their association with changes in brain health and involvement in neurological conditions.
The Formation of Amyloid Plaques
Amyloid plaques are abnormal accumulations found in the spaces between nerve cells in the brain. Their formation begins with a larger protein called amyloid precursor protein (APP), which is embedded within the neuron’s membrane. Normally, APP is processed by enzymes in a way that produces harmless fragments.
However, in certain circumstances, APP is improperly cut by specific enzymes known as beta-secretase and gamma-secretase. This incorrect cleavage generates smaller protein fragments called beta-amyloid peptides. The beta-amyloid 42 (Aβ42) form is particularly prone to clumping together due to its “sticky” nature.
These sticky beta-amyloid fragments then aggregate, initially forming small clusters called oligomers. Over time, these oligomers combine to create larger, insoluble deposits known as amyloid plaques, which reside outside the neurons.
The Development of Tau Tangles
Distinct from plaques, tau tangles form inside nerve cells. The tau protein normally plays a role in stabilizing microtubules, which are like internal railroad tracks within a neuron. These microtubules are responsible for transporting nutrients and other essential molecules from the cell body to distant parts of the neuron.
In the context of disease, tau undergoes an abnormal chemical change called hyperphosphorylation, meaning it acquires too many phosphate groups. This excessive phosphorylation causes the tau protein to detach from the microtubules, destabilizing these crucial internal structures.
Once detached, the hyperphosphorylated tau proteins misfold and aggregate, forming thread-like structures known as paired helical filaments. These filaments then twist and clump together to create neurofibrillary tangles within the neuron’s cytoplasm.
Impact on Brain Function
The presence of amyloid plaques and tau tangles disrupts the brain’s normal operations. Amyloid plaques, located between neurons, interfere with communication signals transmitted across synapses, the junctions where neurons connect and exchange information. This hinders the seamless flow of electrical and chemical messages throughout brain networks.
Plaques also trigger an inflammatory response from the brain’s immune cells, particularly microglia. While microglia clear debris, chronic activation by plaques can lead them to release harmful substances, causing further damage to surrounding neurons. This sustained inflammatory state contributes to widespread cellular dysfunction.
Inside neurons, tau tangles cause the collapse of the microtubule-based transport system. This internal blockage prevents the efficient movement of nutrients, proteins, and other molecules necessary for a neuron’s survival and function. The impairment of this transport system ultimately leads to neuronal dysfunction and, over time, the death of these brain cells.
Role in Neurodegenerative Diseases
Plaques and tangles are recognized as defining hallmarks of Alzheimer’s disease. The accumulation of amyloid plaques is an early event in the disease process, often beginning years or even decades before the onset of noticeable cognitive symptoms.
The progression of tau tangles through the brain, however, correlates more directly with the severity of cognitive decline, including memory loss and other intellectual impairments. The spread of tau pathology mirrors the worsening of symptoms. While Alzheimer’s disease is the most common condition associated with both plaques and tangles, abnormal tau protein accumulation is also a feature of other neurodegenerative disorders.
These other conditions, collectively known as “tauopathies,” include progressive supranuclear palsy, corticobasal degeneration, and certain forms of frontotemporal dementia. In these diseases, tau pathology is a primary driver of neurodegeneration, even if amyloid plaques are not present or are less prominent.
Detection and Therapeutic Approaches
Advancements in medical imaging and fluid analysis now allow for the detection of these protein pathologies in living individuals. Positron Emission Tomography (PET) scans can visualize both amyloid plaques and tau tangles in the brain using specific radioactive tracers. Amyloid tracers detect amyloid, while tau tracers visualize tau tangles.
Cerebrospinal fluid (CSF) analysis offers another method, measuring the levels of specific beta-amyloid peptides and phosphorylated tau protein. Ratios of these markers provide accurate indicators of underlying brain pathology. These diagnostic tools represent a shift from relying solely on post-mortem brain examination for definitive diagnosis.
Therapeutic strategies focus on directly targeting these abnormal proteins. A new class of anti-amyloid monoclonal antibodies has received approval for treating early-stage Alzheimer’s disease. These medications bind to aggregated forms of beta-amyloid, facilitating their clearance from the brain, often by activating the brain’s immune cells.
These anti-amyloid therapies have shown to reduce plaque burden and slow the rate of cognitive and functional decline in individuals with early Alzheimer’s. Research into therapies directly targeting tau pathology is an active area, with ongoing studies exploring approaches that aim to inhibit tau aggregation, stabilize microtubules, or use immunotherapies to clear tau tangles from within neurons.