Amyloid beta and tau are two proteins central to understanding neurodegenerative disorders. While both have constructive roles in a healthy brain, their association with conditions like Alzheimer’s disease has made them subjects of intense research. The transformation of these proteins from a normal to a pathological state can drive the progression of brain diseases.
Normal Functions of Amyloid and Tau Proteins
Amyloid beta is a peptide fragment derived from the Amyloid Precursor Protein (APP). When APP is cleaved by enzymes, it produces amyloid beta fragments that are cleared away in a healthy brain. Research suggests these soluble peptides have physiological roles, such as regulating synaptic signal transmission, contributing to neural repair, and protecting the brain from oxidative stress.
The tau protein functions as a stabilizing component for microtubules within neurons. Microtubules act as a microscopic highway system, transporting essential cargo like nutrients and neurotransmitters from the neuron’s cell body down the axon. Tau binds to these microtubules, ensuring their stability and the efficient function of this internal transport system.
Pathological Transformation into Plaques and Tangles
The pathological transformation of amyloid beta begins when the fragments misfold and stick to one another instead of being cleared. They first form small, soluble clusters called oligomers, which are considered the most toxic form of amyloid beta. Over time, these oligomers aggregate into the large, insoluble amyloid plaques that form in the spaces between neurons.
A different process affects tau proteins. In certain brain diseases, tau undergoes hyperphosphorylation, where excessive phosphate groups attach to it. This alteration changes tau’s shape, causing it to detach from microtubules and compromise the neuron’s internal transport system. The abnormal tau proteins then aggregate inside the neuron, forming insoluble, fibrous clumps known as neurofibrillary tangles (NFTs) that disrupt cellular processes.
The Interplay Between Amyloid Beta and Tau
A leading explanation for how amyloid and tau pathologies are connected is the “Amyloid Cascade Hypothesis.” This model proposes that the accumulation of amyloid beta, particularly soluble oligomers, is the initiating event. The buildup of these toxic amyloid fragments in the extracellular space is thought to trigger a cascade of harmful downstream effects within the neurons.
According to this hypothesis, pathological amyloid beta activates specific enzymes, known as kinases. These kinases, in turn, add an excessive number of phosphate groups to tau proteins. This hyperphosphorylation causes tau to detach from microtubules and form neurofibrillary tangles inside the cell, placing amyloid beta upstream of tau in the disease process.
The interaction can also create a feedback loop, as evidence suggests established tau pathology can exacerbate amyloid toxicity. This interconnected pathway of plaque and tangle development results in widespread neuronal injury and death.
Consequences for Brain Health
The combination of extracellular plaques and intracellular tangles impairs neuronal communication. Plaques and toxic oligomers interfere with signal transmission at the synapse. Inside the cell, tau tangles and the collapse of the microtubule network cripple the neuron’s transport system, leading to a breakdown of its structure and function.
This dysfunction and internal collapse culminate in the death of neurons, causing affected brain regions to shrink in a process known as brain atrophy. The location of this cell death correlates with clinical symptoms. For instance, neuronal loss in the hippocampus leads to the memory loss seen in Alzheimer’s, while progressive loss across the cerebral cortex results in a broader decline in cognitive functions, including problems with language, reasoning, and orientation.
Targeting Amyloid and Tau for Treatment
Therapeutic strategies often target these two pathologies. Anti-amyloid treatments are designed to reduce amyloid beta in the brain. One approach uses monoclonal antibodies, like lecanemab and donanemab, which bind to amyloid beta and help the brain’s immune cells clear it. These therapies aim to remove existing plaques and prevent new ones from forming.
Researchers are also developing therapies aimed at the tau protein. Strategies include developing inhibitors for the kinase enzymes that hyperphosphorylate tau, thereby preventing its detachment from microtubules and subsequent aggregation. Other approaches focus on preventing misfolded tau from clumping together or using immunotherapies to clear existing tangles. Given their interconnected relationship, combination therapies targeting both amyloid and tau may prove more effective.