The mainstream of the Alzheimer's research community remains primarily interested in clearing deposits of amyloid-β from the aging brain. That said, there is a growing interest in tackling tau aggregation as well, particularly given the long years of failure to achieve meaningful results through clinical trials of immunotherapies that target amyloid-β. The current consensus on the development of the disease is that increased amyloid-β, leading to solid deposits of amyloid in and between cells, is an early phenomenon, and may in and of itself do little more than create mild cognitive impairment. However, amyloid-β aggregation sets the stage for the later production of neurofibrillary tangles, consisting of an altered form of tau protein, and these are far more harmful to brain function.
Both tau and amyloid-β protein aggregates are biochemically complex, with a surrounding halo of many varieties of harmful molecule. It is the halo rather than the deposits that do the damage to brain cells and their function, or so present thinking goes. Further, more recent research suggests that while tau is the more harmful of the two, tau synergizes with amyloid-β to causes greater damage than it would on its own.
This view of the condition may explain why attempting to intervene late in the process with anti-amyloid therapies fails to produce sizable benefits, but nonetheless does appear to help to some degree, particularly in animal models. So perhaps amyloid-β clearance as an approach is best harnessed for prevention or slowing of early development of the condition. Still, that leaves the challenge of treating later stages of the condition for present patients, and thus a growing number of researchers are working on ways to remove tau aggregates. Many of those scientists advocate for the development of therapies that clear both tau and amyloid-β at the same time, a strategy that seems very reasonable given the evidence to date.
A new study sheds light on how the hallmarks of Alzheimer's disease - amyloid-beta (A-beta) plaques and neurofibrillary tangles containing the protein tau - produce their damaging effects in the brain. The findings suggest that strategies directed against both pathologic proteins, rather than one or the other, might be promising therapeutic options. "Our current study reinforces growing evidence suggesting that A-beta and tau work together to impair brain function and that, for certain aspects of that impairment, tau predominates. We are intrigued to learn how they are interacting at a molecular level, in order to find ways of blocking that synergy."
Studies with two mouse models that overexpress different forms of tau found, for the first time, that elevated levels of the protein were associated with a significant reduction in neural activity whether or not tau had aggregated into tangles. Experiments with a novel mouse model that overexpresses both A-beta and tau found that, in the presence of both pathological proteins, A-beta-associated hyperactivity was abolished and tau's neuronal silencing effect predominated. The findings were duplicated in mice regardless of their age, including animals too young to exhibit the loss of neurons typically seen in animals that only overexpress tau.
The authors note that their findings could help explain why clinical trials of A-beta-blocking therapies have had difficulty improving symptoms of patients with Alzheimer's disease. "One implication of our work is that approaches combining anti-A-beta and anti-tau therapies might be more effective than either alone, at least from the perspective of neural activation. Finding that tau and A-beta work in a synergistic fashion opens the doors to new research into understanding exactly how that interaction works."
The coexistence of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the neocortex is linked to neural system failure and cognitive decline in Alzheimer's disease. However, the underlying neuronal mechanisms are unknown. By employing in vivo two-photon Ca2+ imaging of layer 2/layer 3 cortical neurons in mice expressing human Aβ and tau, we reveal a dramatic tau-dependent suppression of activity and silencing of many neurons, which dominates over Aβ-dependent neuronal hyperactivity.
We show that neurofibrillary tangles are neither sufficient nor required for the silencing, which instead is dependent on soluble tau. Surprisingly, although rapidly effective in tau mice, suppression of tau gene expression was much less effective in rescuing neuronal impairments in mice containing both Aβ and tau. Together, our results reveal how Aβ and tau synergize to impair the functional integrity of neural circuits in vivo and suggest a possible cellular explanation contributing to disappointing results from anti-Aβ therapeutic trials.