A new Columbia study has found clues of Alzheimer's beginnings, revealing how tau filaments-protein clumps that are closely linked to memory decline in Alzheimer's disease-get their start. The finding raises the prospect of future Alzheimer's drugs that could stop the production of the filaments at its source.
Amyloid plaques are often thought to be the main villains in Alzheimer's disease, but tau aggregates-tangles of stringy tau proteins-are more strongly linked with memory loss and cognitive decline. The latest Alzheimer's drugs, amyloid-clearing antibodies that modestly slow cognitive decline, have disappointed researchers, prompting several companies to develop drugs that target tau.
Pinpointing the origins of how tau misfolds into the specific filaments that make up the tangles had been elusive for decades. One reason is that tau does not misfold in Alzheimer's animal models the same way it does in people. To study the tangles seen in human disease, researchers studying tau often take tangles from patient brains and inject them into animals.
"These prior studies could not capture how tau misfolds in the first place in Alzheimer's Disease, but understanding how tau aggregation begins is critical if we want to create therapies that prevent neurodegeneration before it starts," says the new study's senior author, Kapil Ramachandran, assistant professor of neurological sciences (in neurology, in neuroscience and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain).
The new Columbia research shows in mice that disruptions to a recently discovered garbage disposal system in neurons triggers the formation of tau paired helical filaments, the primary component of tau tangles. While tau can adopt different shapes and filaments that are characteristic of various neurodegenerative diseases, the filaments formed in the Columbia study appear nearly indistinguishable at a macroscopic level from the filaments seen in people with Alzheimer's disease.
Tau disposal
Ramachandran's new finding got its own start when, as a graduate student, he unexpectedly discovered that neurons have a second garbage disposal system.
The cell's well-known disposal system (the proteasome) chews up old or damaged proteins into smaller parts that are then recycled into newer proteins.
Kapil Ramachandran
Ramachandran found that neurons in the brain-and seemingly only neurons-have an extra disposal in an unusual location, straddling the neuron's outer membranes. "We had lots of questions but the most fundamental was, what does this thing do? I've been working on it ever since," he says.
Ramachandran previously found that the extra disposal (he dubbed it the neuroproteasome) only chews up a neuron's newborn proteins, which are highly vulnerable to misfolding as they come off the cell's protein factory.
"In our new study, we wanted to see what would happen if we blocked the neuroproteasome, looking very broadly. We had to build a set of molecular tools to make that happen," he says. "And that's when we found the tau filaments."
A connection with ApoE
Disrupting the neuroproteasome alone rapidly triggers the misfolding of tau into the filaments seen in Alzheimer's brains.
Ramachandran's team dug deeper to look for factors that modify the extra disposal machinery, and found that the ApoE protein, a genetic risk factor for Alzheimer's, controls the neuroproteasome.
The type of ApoE protein has a dramatic effect on the disposal, changing the number of disposal units in a neuron's membrane. ApoE4, the version known to double the risk of developing Alzheimer's, reduces the number of disposals, leading to a dramatic increase in susceptibility to develop tau aggregates. ApoE2, a variant known to reduce the risk of Alzheimer's, does the opposite, increasing the number of disposal units and reduces the susceptibility for tau aggregation.
These same patterns were seen in human brain tissue: People with two copies of APOE4 had many fewer neuroproteasomes in their brains than other people and more neuroproteasomes were found in brain regions that are generally more resilient to tau aggregation in Alzheimer's. Neuroproteasomes also declined with increasing age.
"The links between tau filament formation and ApoE variants and aging, Alzheimer's greatest risk factors, suggest we may have found a mechanism to explain how an important aspect of the disease gets started," Ramachandran says. "Our hope now is that our findings open a whole new area of research that eventually helps patients."
