New findings from Emory University are challenging existing theories about the origins of Alzheimer’s, a leading cause of dementia in older adults worldwide. A research team from the Goizueta Brain Health Institute has found strong evidence supporting a new understanding of the mechanisms underlying Alzheimer’s disease. Drs. Todd Golde and Yona Levites explain how deposits of beta amyloid, long known to accumulate in the brains of Alzheimer’s patients, serve as a kind of scaffolding for the accumulation of other proteins. Since many of these proteins have known signaling functions, their presence around amyloid buildups, known as plaques, may be the cause of brain cell damage rather than the amyloid itself. In the brains of those with Alzheimer’s, amyloids accumulate and turn into plaques that disrupt brain function and cause cognitive decline.
The big unknown has been exactly how this happens. According to the most widely held hypothesis, amyloid beta buildup disrupts cell-cell communication and activates immune cells in a process that ultimately destroys brain cells. In the study, the researchers put forward a new hypothesis, emphasizing a different role for amyloid beta, a simple protein that forms in all brains but normally dissolves through natural processes. In experiments, they identified and measured the levels of more than 8,000 proteins in human brains with Alzheimer’s, as well as similar proteins in mice. Focusing on the proteins whose levels increased most dramatically, they identified more than 20 proteins that co-accumulate with amyloid beta in both human brains with Alzheimer’s and mice. Significantly more types of amyloid buildup than amyloid beta have been implicated in more than 30 human disorders that affect body tissues and organs.
Scientists therefore believe that the initial notion of a purely linear amyloid cascade is now recognized as simplistic. Studies have unraveled the vast complexity of changes that occur over decades in the brains of individuals as Alzheimer’s-related pathologies emerge. They call this the “amyloid scaffolding hypothesis” and posit that if amyloid deposits provide the scaffolding for the accumulation of numerous proteins, then perhaps the accumulation of these proteins mediates downstream pathophysiology. Of course, the amyloid “scaffolding” and amyloid-as-a-directed-toxin hypotheses are not mutually exclusive. Many proteins that interact with amyloid may be involved in clearing, coating, and neutralizing the structure to reduce toxicity, or in combination. Other components may simply be bystanders, but once present, they may still alter signaling gradients. But this is not the only new development in the field of Alzheimer’s that ties in with this research.
Researchers at the Max Planck Institute for Multidisciplinary Sciences have now shown that, in addition to neurons, special glial cells in the brain also produce beta-amyloid. Until now, it was thought that neurons were the main producers of beta-amyloid and that they were the main target of new drugs. Instead, the Max Planck scientists have discovered that oligodendrocytes, the cells that produce myelin around nerves, are also capable of synthesizing amyloid. Cells in the nervous system produce beta-amyloid by splitting a larger precursor molecule with the help of an enzyme called BACE1. For their experiments, the researchers specifically eliminated BACE1 in neurons and oligodendrocytes of mice. Oligodendrocytes lacking BACE1 developed around 30% fewer plaques. Knocking out the BACE1 gene in neurons reduced plaque formation by more than 95%. Plaque deposits form only when a certain amount of neuronal amyloid beta is present.
Oligodendrocytes therefore contribute to these plaques. Last year, the same team published results showing that myelin dysfunction drives the accumulation of amyloid beta, suggesting a similarity in origin between Alzheimer’s and myelin-damaging diseases such as multiple sclerosis. Mechanistically, myelin dysfunction causes the cellular machinery that produces Aβ to accumulate within axonal swellings and increases the breakdown of cortical amyloid precursor protein (b-APP). Surprisingly, Alzheimer’s mice with dysfunctional myelin lack plaque-blocking microglia. In the study, despite successful induction, disease-associated amyloid (DAM) microglia, which normally clear amyloid plaques, was apparently distracted by damage to the surrounding myelin. It would not be surprising if it were demonstrated that the cellular damage that causes the accumulation of amyloid is not at the expense of neurons, as always thought, or relying on microglia (the local immune system), but requires oligodendrocytes as well.
Even more surprising, if it were demonstrated that Alzheimer’s disease is a variant of multiple sclerosis that affects only cognitive functions. Only science will give the final answer.
Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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