A3 Alzheimer's (amyloid plaques, tau tangles)

Topic

The neuron is the focal point of Alzheimer's disease, a condition characterized by a cascade of protein aggregation that attacks the neuron on two distinct fronts, ultimately reducing synaptic density before causing neuronal death. The first front involves the extracellular space surrounding the neuron, where beta-amyloid accumulates; this accumulation depends on the balance between beta-amyloid production and its physiological clearance. When beta-amyloid production exceeds the neuron's clearance capacity, the protein is no longer eliminated at the same rate it is generated and begins to accumulate steadily around the neuron.

This accumulation of beta-amyloid around the neuron does not occur uniformly but rather in two successive stages: first, small aggregation nuclei form, and subsequently, these nuclei grow by incorporating more beta-amyloid to form larger aggregates. As more beta-amyloid accumulates around the neuron, more of these aggregates form; upon contact with the neuron's interior, these beta-amyloid aggregates activate a group of kinases capable of chemically modifying another protein—tau—which had not previously been involved in the process.

Inside the neuron, this group of kinases—activated by the beta-amyloid aggregates—hyperphosphorylates the tau protein; that is, it adds an excess of phosphate groups, thereby altering the protein's normal behavior. Hyperphosphorylated tau protein loses its usual function and instead aggregates with other hyperphosphorylated tau molecules, forming structures known as neurofibrillary tangles within the neuron. The more the tau protein becomes hyperphosphorylated, the faster neurofibrillary tangles grow within the neuron.

Both the accumulation of beta-amyloid around the neuron and the growth of neurofibrillary tangles inside it converge on the same effect: both processes reduce the neuron's synaptic density—the point where the two cascades mentioned at the outset meet. The greater the beta-amyloid accumulation and the more advanced the neurofibrillary tangles, the lower the neuron's remaining synaptic density, thereby reducing its ability to communicate with other neurons.

When the neuron's synaptic density drops sufficiently, the neuron dies; this neuronal death is proportional to the load of neurofibrillary tangles accumulated within it: the more tangles the neuron contains, the higher the likelihood of its death. This process, occurring across many neurons simultaneously, translates clinically into progressive cognitive decline, as each dying neuron ceases to contribute the synaptic density and communication that sustained cognitive functions before Alzheimer's disease began to affect the cell.

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