In the research linked below, scientists describe a potentially beneficial point of interference in a tau-related mechanism of neurodegeneration: targeted sabotage of this mechanism can restore lost cognitive function and otherwise turn back some of the effects of a tauopathy, at least in the engineered mouse lineages used. Tauopathies are neurodegenerative conditions characterized by an accumulation of altered forms of tau protein, forming solid fibrils and tangles in brain tissue. Alzheimer's disease is perhaps the most familiar of these conditions, and there is still considerable debate over the degree to which the harm to brain cells and cognitive function is caused by amyloid-β versus tau in that case. For both proteins the situation is somewhat similar: a lot of work focused on how the deposited solid aggregates relate to mechanisms of cell death and dysfunction, as well as why it is that older people have more of these aggregates, and so far frustratingly limited progress towards therapies capable of clearing out these forms of metabolic waste, despite years of large-scale investment. Many researchers are, however, focused less on clearance than on altering the operation of brain biochemistry in the presence of tau and amyloid: finding ways to short-circuit the worst consequences rather than finding ways to remove the root causes. I can't say I think that this is a wise high-level strategy, but it is very prevalent in the research community.
Why does the presence of the insoluble form of tau increase with age? One possibility is shared with amyloid, that the clearance and filtration mechanisms operating on cerebrospinal fluid decline in later life. That might include dysfunction in the choroid plexus, responsible for filtration, or dysfunction in the drainage system of small fluid passageways behind the nose. The creation and removal of these aggregates is actually fairly dynamic, and the outcome only looks like a slow and steadily increase because the imbalance between that creation and removal grows slowly and steadily. Another possible cause of growing levels of tau is the age-related decline in immune function, just as apparent in the brain as elsewhere in the body. Immune cells are responsible for clearing out waste, among many other tasks, and when they are less efficient we might expect levels of all forms of waste between cells to increase. At the detail level of biochemistry and mechanisms, however, a great deal of uncertainty remains. There is considerable debate and a great deal of published research covering efforts to catalog how and why the presence of tau increases with age, and how and why it does so to a larger degree in only some people. It is a complex field, still in progress towards definitive answers.
In the ideal world, this lack of knowledge could be treated as a Gordian Knot and cut with some form of therapy that efficiently removed tau aggregates. That would very quickly and clearly pin down the importance of the role of tau in neurodegenerative disease and cell death. It isn't the chosen strategy for much of the research community, however, and there is typically more of a focus on the class of approach illustrated below, in which downstream mechanisms in a disease brain are mapped and then manipulated. The root cause remains, able to cause harm via any of the other, yet to be mapped consequences: keeping a damaged machine running without repairing that damage is typically much harder than just focusing on repair. It is possible to achieve beneficial outcomes by following this strategy, as is the case here, but they will typically only deal with a fraction of the issue or only slow the progression of the condition. Still, within the context of the strategy chosen here, and with the caveat that work in mouse models for amyloid and tau pathologies has a poor record of success when it comes to making the leap to human medicine, this seems promising. Those in the audience who have followed research into Alzheimer's and amyloid-β over the past decade might find that there are a number of parallels in the results presented here and some of the discoveries made of how amyloid gives rise to harmful effects on cells - also quite indirect in its relationship with the aggregrated solid form of the protein.
Using a mouse model of tauopathy that produces a mutated form of human tau protein, researchers correlated memory deficits with the presence of a fragment of the tau protein. The tau fragment, which is produced when caspase-2 cuts the full-length tau protein at a specific location, was also found at higher levels in the brains of Alzheimer's disease patients compared to healthy individuals of the same age. While the standard hallmark of tauopathies is the appearance in brain tissue of large tangles of abnormal tau protein, it has recently become less clear whether the tangles of tau are actually causing cognitive decline. "In the past, many studies focused on the accumulation of tangles and their connection to memory loss, but the more we learn, the less likely it seems that they are the cause of disease symptoms. The pathological fragment of tau that we have identified resists forming tangles and can instead move freely throughout the cell. Therefore, we decided to look for other mechanisms that could affect synaptic function."
The researchers used fluorescent labeling to track and compare the behavior of normal and mutated tau in cultured neurons from the rat hippocampus, the brain region most associated with learning and memory. Unlike normal tau, both mutated tau and the short fragment produced when caspase-2 cuts tau were primarily found within structures called dendritic spines, where neurons receive inputs from neighboring cells. The overabundance of mutated tau, including the caspase-2-produced fragment, caused disruptions in synaptic function in the spines. The impact on synapses was specific, with no observed effects on the overall structure or survival of the neurons. "It appears that abnormally processed tau is disrupting the ability of neurons to properly respond to the signals that they receive, producing memory deficits independent of tangle formation. Because this effect is occurring without cell death or a loss of synapses, we have a better chance of intervening in the process and hopefully reversing symptoms of the disease."
In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.