Alvin Gogineni, Genentech
Alvin Gogineni, Genentech

Catching the Memory Thief

by Alan Dove

For more than a century, scientists have dedicated themselves to figuring out what drives Alzheimer’s disease. Named for Alois Alzheimer, the German psychiatrist and neuropathologist who first described a case in 1906, this debilitating neurodegenerative condition is the most common cause of dementia in older adults and a leading cause of death in industrialized countries. Hallmarks of the disease include two abnormal structures in the brain: plaques made from short protein fragments called amyloid beta peptides, and tangles of a heavily modified version of the common brain protein tau.

Though some researchers have debated which of the two structures—amyloid plaques or tau tangles—is more important, Li Gan refuses to take sides. “The definition of Alzheimer’s includes amyloid plaques and neurofibrillary tangles, so by definition both are important,” says Gan, who is director of the Helen and Robert Appel Alzheimer’s Disease Research Institute and the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.

Major breakthroughs in Gan’s laboratory are now transforming our understanding of the disease.

The Tau of Neurodegeneration

Besides the disease definition, Gan points to large bodies of research supporting crucial roles for both beta-amyloid plaques and tau tangles in Alzheimer’s disease pathogenesis. Mutations in the gene for amyloid precursor protein, the source of beta-amyloid peptides, confer a higher risk of developing the disease. Meanwhile, brain-imaging scans show that the accumulation of tau tangles correlates directly with cognitive decline in patients.

“Tau pathology could be caused by, or could be downstream of, amyloid, meaning when you have high amyloid, it could facilitate or exacerbate tau pathology,” Gan says, adding that “I view tau almost like an executioner.”

That's only when tau goes rogue, though. In healthy brains, it helps maintain the structural proteins and normal activity within neurons. Its transformation from maintenance worker to executioner stems from chemical changes to the protein.

Researchers have long known that tau in pathological tangles is decorated with many more phosphate molecules than normal tau, and that change has been the focus of extensive research. The phosphorylation difference alone, though, didn’t seem to account for the full spectrum of changes in tau’s activity.

Using cultured cell models of Alzheimer’s disease, Gan’s laboratory discovered a critical additional modification of tau: the attachment of acetyl groups to specific amino acids in the protein. “Acetylation will change protein-protein interaction on the biochemical level, and it will prevent tau from being degraded, especially if it’s misfolded,” Gan says. Subsequent studies by other groups have confirmed that pathological tau tangles in the brains of Alzheimer’s disease patients indeed contain heavily acetylated tau.

Proteins often fail to fold into their correct shapes, either while being produced in the cell or as a result of subsequent modifications. Normally, an elaborate network of sensors and checkpoints in the cell detects these misfolded proteins and attaches a chemical flag that directs them into a disposal system. The acetyl groups Gan discovered on tau form a sort of armor that blocks this process. As a result, defective tau proteins that should be flagged and broken down instead persist, and their aberrant interactions allow them to accumulate in deadly tangles.

“Having this kind of platform allows functional genomics to be done in the human neurons and human microglia.”

Back to the Future

Such detailed mechanistic insights, which are essential for identifying new ways to treat Alzheimer’s disease, have been hard to come by. Animal models don’t correlate perfectly with human disease, and in humans the condition takes decades to develop and can be analyzed in detail only after the patient dies. To get around those problems, Gan’s laboratory has pioneered a third approach, using human stem cells to replicate various disease states in Petri dishes.

The standard approach to working with such cells, called induced pluripotent stem cells, is to isolate ordinary cells, such as skin cells, from a patient, then treat them with specific growth factors, causing them to revert to an earlier developmental state. Having rewound the developmental clock, scientists can then advance it on a different timeline, using a different set of growth factors to induce the cells to develop into other types of tissues, such as neurons. Because they still carry the patient’s genome, the stem cell–derived tissues can recapitulate whatever genetic conditions the patient may have.

Stem cell–derived neurons are essentially copies of the patient’s own neurons, which investigators can then study up close. Unfortunately, the same gene mutations that contribute to Alzheimer’s disease can also interfere with normal neuronal differentiation from stem cells. “Sometimes the differentiation will be influenced by those mutations, so it confounds the results,” Gan says.

“We wanted to take the guesswork out of the equation, so the way we do it is we put a transcriptional factor into the stem cells that is driven by [the antibiotic] doxycycline, so then if we just add doxycycline, every cell will be expressing the fate-determination factors for a short period of time, and that way it will become the same neuron type, regardless of its mutations,” Gan says.

The efficiency and uniformity of this approach has allowed the lab to adopt another new technology, the CRISPR gene-editing system. CRISPR allows Gan and her colleagues to systematically inactivate each gene in a cell type to see what effect it has. “Having this kind of platform allows functional genomics to be done in the human neurons and human microglia,” Gan says.

A Delicate Balance

Microglia, the main immune cells of the brain, might seem like an odd focus for a lab that studies a disease of neuron degeneration. However, findings by Gan and others in the field increasingly point to the immune system as a critical component of Alzheimer’s disease pathogenesis.

“Amyloid deposition occurs many decades before cognitive decline,” Gan says. Even the later stage of the disease, when tau accumulates in neurofibrillary tangles, can persist for years before patients exhibit any symptoms. “So, one of the major questions of my lab is to understand what is the switch? What has driven the brain from being able to deal with pathological buildups but still function normally, to not being able to function normally?”

The chief job of the immune system is to defend against invaders, real or perceived, and return the body to a stable state of homeostasis. According to recent results from Gan and her collaborators, that’s exactly what breaks down in the late stages of Alzheimer’s disease. Initially, the immune system adjusts to the buildup of amyloid plaques and tau tangles as the disease progresses. Then eventually, at a later stage of disease, the innate immune system overreacts, leading to the destruction of neurons.

Gan has traced the trouble to the interferon response system, one of the body’s major defenses against viruses. In Alzheimer’s disease, DNA fragments released into the cytoplasm of damaged cells likely get mistaken for invading viral genomes, triggering the interferon response and setting off a microglial rampage that destroys the neurons.

“If we can somehow suppress this antiviral hyperactivation, we can enhance cognitive resilience,” Gan says.

By preventing the switch from homeostasis to neurodegeneration, such an approach could delay or stop cognitive decline even in patients with heavy loads of plaques and tangles. Her team is now investigating ways to do that, ideally with small-molecule drugs. She adds that “this is potentially the most targetable component of our body.”

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