(NIH) Alzheimer’s disease disrupts critical metabolic processes that keep neurons healthy. These disruptions cause nerve cells in the brain to stop working, lose connections with other nerve cells, and finally die. The destruction and death of nerve cells causes the memory failure, personality changes, problems in carrying out daily activities, and other features of the disease.
The brains of people with AD have an abundance of two abnormal structures—amyloid plaques and neurofibrillary tangles—that are made of misfolded proteins (see “Protein Misfolding” for more information). This is especially true in certain regions of the brain that are important in memory.
The third main feature of AD is the loss of connections between cells. This leads to diminished cell function and cell death.
Amyloid plaques are found in the spaces between the brain’s nerve cells. They were first described by Dr. Alois Alzheimer in 1906. Plaques consist of largely insoluble deposits of an apparently toxic protein peptide, or fragment, called beta-amyloid.
We now know that some people develop some plaques in their brain tissue as they age. However, the AD brain has many more plaques in particular brain regions. We still do not know whether amyloid plaques themselves cause AD or whether they are a by-product of the AD process. We do know that genetic mutations can increase production of beta-amyloid and can cause rare, inherited forms of AD (see “Genes and Early-Onset Alzheimer’s Disease” for more on inherited AD).
To view a video showing what happens to the brain in AD, go to www.nia.nih.gov/alzheimers/ADvideo.
From APP to Beta-Amyloid Plaques
Amyloid precursor protein (APP), the starting point for amyloid plaques, is one of many proteins associated with the cell membrane, the barrier that encloses the cell. As it is being made inside the cell, APP becomes embedded in the membrane, like a toothpick stuck through the skin of an orange.
In a number of cell compartments, including the outermost cell membrane, specific enzymes snip, or cleave, APP into discrete fragments. In 1999 and 2000, scientists identified the enzymes responsible for cleaving APP. These enzymes are called alpha-secretase, beta-secretase, and gamma-secretase. In a major breakthrough, scientists then discovered that, depending on which enzyme is involved and the segment of APP where the cleaving occurs, APP processing can follow one of two pathways that have very different consequences for the cell.
In the benign pathway, alpha-secretase cleaves the APP molecule within the portion that has the potential to become beta-amyloid. This eliminates the production of the beta-amyloid peptide and the potential for plaque buildup. The cleavage releases from the neuron a fragment called sAPPα, which has beneficial properties, such as promoting neuronal growth and survival. The remaining APP fragment, still tethered in the neuron’s membrane, is then cleaved by gamma-secretase at the end of the beta-amyloid segment. The smaller of the resulting fragments also is released into the space outside the neuron, while the larger fragment remains within the neuron and interacts with factors in the nucleus.
In the harmful pathway, beta-secretase first cleaves the APP molecule at one end of the beta-amyloid peptide, releasing sAPPβ from the cell. Gamma-secretase then cuts the resulting APP fragment, still tethered in the neuron’s membrane, at the other end of the beta-amyloid peptide. Following the cleavages at each end, the beta-amyloid peptide is released into the space outside the neuron and begins to stick to other beta-amyloid peptides. These small, soluble aggregates of two, three, four, or even up to a dozen beta-amyloid peptides are called oligomers. Specific sizes of oligomers may be responsible for reacting with receptors on neighboring cells and synapses, affecting their ability to function.
It is likely that some oligomers are cleared from the brain. Those that cannot be cleared clump together with more beta-amyloid peptides. As the process continues, oligomers grow larger, becoming entities called protofibrils and fibrils. Eventually, other proteins and cellular material are added, and these increasingly insoluble entities combine to become the well-known plaques that are characteristic of AD.
For many years, scientists thought that plaques might cause all of the damage to neurons that is seen in AD. However, that concept has evolved greatly in the past few years. Many scientists now think that oligomers may be a major culprit. Many scientists also think that plaques actually may be a late-stage attempt by the brain to get this harmful beta-amyloid away from neurons.
The second hallmark of AD, also described by Dr. Alzheimer, is neurofibrillary tangles. Tangles are abnormal collections of twisted protein threads found inside nerve cells. The chief component of tangles is a protein called tau.
Healthy neurons are internally supported in part by structures called microtubules, which help transport nutrients and other cellular components, such as neurotransmitter-containing vesicles, from the cell body down the axon.
Tau, which usually has a certain number of phosphate molecules attached to it, binds to microtubules and appears to stabilize them. In AD, an abnormally large number of additional phosphate molecules attach to tau. As a result of this “hyperphosphorylation,” tau disengages from the microtubules and begins to come together with other tau threads. These tau threads form structures called paired helical filaments, which can become enmeshed with one another, forming tangles within the cell. The microtubules can disintegrate in the process, collapsing the neuron’s internal transport network. This collapse damages the ability of neurons to communicate with each other.
Loss of Connection Between Cells and Cell Death
The third major feature of AD is the gradual loss of connections between neurons. Neurons live to communicate with each other, and this vital function takes place at the synapse. Since the 1980s, new knowledge about plaques and tangles has provided important insights into their possible damage to synapses and on the development of AD.
The AD process not only inhibits communication between neurons but can also damage neurons to the point that they cannot function properly and eventually die. As neurons die throughout the brain, affected regions begin to shrink in a process called brain atrophy. By the final stage of AD, damage is widespread, and brain tissue has shrunk significantly.
National Institute on Aging