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Untangling a cause of memory loss in neurodegenerative diseases
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"The current evidence suggests that preventing caspase-2 from cleaving tau could potentially reverse existing deficits and restore cognition, warranting efforts to develop appropriate drugs to inhibit this protease."
Wednesday, October 12, 2016
NIH-funded mouse study identifies a possible therapeutic target for a family of disorders.
Tauopathies are a group of neurodegenerative disorders, including Alzheimer's disease that are characterized by the deposition of aggregates of the tau protein inside brain cells. A new study reveals that the cutting of tau by an enzyme called caspase-2 may play a critical role in the disordered brain circuit function that occurs in these diseases. Of interest, the culprit tau fragment identified in this study is actually resistant to forming aggregates, and it causes a disturbance in memory function in animal models before brain cell loss occurs.
In mice genetically engineered to mimic aspects of human tauopathy disorders, the researchers restored some of the learning and memory deficits by blocking caspase-2 activity, which suggests that some of the cognitive loss seen in tauopathies might be reversible. The study was funded by the National Institutes of Health's National Institute of Neurological Disorders and Stroke (NINDS) and published in the journal Nature Medicine.
"The results of this exciting study suggest that the cognitive loss that occurs in tauopathy may be reversed by blocking the function of caspase-2," said Roderick A. Corriveau, Ph.D., a program director at NINDS. "This motivates further investigation of caspase-2 as a novel therapeutic target for dementia."
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," said Karen H. Ashe, M.D., Ph.D., professor of neurology at the University of Minnesota and senior author of this study, "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."
To do this, Dr. Ashe's group 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," said Dr. Ashe. "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."
Dr. Ashe and her team are now planning additional experiments to uncover the mechanisms by which abnormally processed mutant tau produces memory deficits.
The study was supported by the NIH (NS63214 and NS79374) with additional funding provided by the T. and P. Grossman Family Foundation, B. Grossman, and K. Moe.
The NINDS the nation's leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit
Zhao et al. "Caspase-2 cleavage of tau reversibly impairs memory." Nature Medicine. October 10, 2016. DOI: 10.1038/nm.4199
Caspase-2 cleavage of tau reversibly impairs memory
Nature Medicine
(Oct 10 2016)
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.
Tau is a neuronal protein that stabilizes microtubules1, 2; however, it is also found in cellular compartments that lack microtubules, such as dendritic spines and the extracellular space3, 4, suggesting that it may have other roles, such as acting as a signaling molecule. The observations that tau interacts with Fyn kinase and NMDA receptors located in dendritic spines support the idea that it regulates synaptic physiology3. In neurological disorders, abnormally phosphorylated forms of tau aggregate into insoluble fibrils that accumulate in the soma and dendrites of neurons. Tau fibrils have been associated with disrupted kinesin protein function and axonal transport5, as well as with direct cytotoxicity6. In the brain, the assembly of tau to form neurofibrillary tangles occurs rapidly, usually within a day; however, once formed they persist indefinitely7. In humans with AD the percentage of neurons containing neurofibrillary tangles parallels the duration of overt symptoms, increasing from 0.1% to 17% over a period of two decades8. In mice the electrophysiological properties of neurons are unaffected by the presence of neurofibrillary tangles9; global neural network dysfunction occurs in mice with modest numbers of neurofibrillary tangles10, and both memory deficits and neuron death can be dissociated from these fibrillar inclusions11. The sparseness and inertness of neurofibrillary tangles led us to hypothesize that neural network disruption and cognitive symptoms may be caused by soluble forms of tau disrupting synaptic function. Here we describe a mechanism that regulates the missorting of soluble tau to dendritic spines, impairing memory function in the mammalian brain.
Here we describe a novel pathogenic process involving caspase-2 cleaving tau at Asp314, forming Δtau314, which reversibly impairs memory function. We show that reducing levels of caspase-2 results in recovery of existing memory deficits, and that cleavage of tauP301Lby caspase-2 is necessary to drive tau to dendritic spines, reduce excitatory synaptic transmission and induce memory deficits in mice. The exact mechanism by which the generation of Δtau314 promotes the missorting of full-length tau is unclear, but it may involve Δtau314 functioning at extracellular or intracellular sites.
In rTg4510 mice, tau forms neurofibrillary tangles, which function like self-propagating assemblies, as they continue to accumulate even when human tau expression is repressed11. Unexpectedly, following tau suppression memory function in rTg4510 mice recovers, implying that the mechanism of recovery involves the elimination of nonfibrillar forms of tau, which our current results support. The genetic background of the strain influences memory function in rTg4510 mice; rTg4510 on a mixed C57B6J/FVBN/129S6 background showed no significant transgene effect at 16 months of age and lacked Δtau314 (K.H.A., unpublished data), suggesting genetic modulation of caspase-2 activity.
The implication of caspase-2 in tau pathogenesis is intriguing given its role in aging and neurodegeneration (reviewed in ref. 23). Caspase-2 is related to the product of the primordial apoptosis gene ced-3 (ref. 24), but it has evolved to perform a number of diverse other roles. Some potentially relevant non-apoptotic roles include regulating autophagy25, oxidative stress26 and endoplasmic reticulum stress27. Caspase-2 also mediates neuronal dysfunction in mice expressing disease-linked variants of amyloid precursor protein (APP)28 and huntingtin29, but unlike in rTg4510 mice, its effects in these models do not involve cleaving the mutant transgene products. The translocation of the small GTPase RhoA and its effector kinase ROCKII to dendritic spines requires caspase-2, and this effect has been proposed to explain the dependence of APP-induced cognitive deficits on caspase-2 (ref. 28). Caspase-2-null mice expressing mutant huntingtin were protected from developing behavioral deficits29. In neither of these mouse models is the target of caspase-2 known. An intriguing question is whether the cleavage of tau by caspase-2 mediates APP- and huntingtin-induced synaptic deficits.
In addition to Asp314, tau contains two previously reported caspase cleavage sites, Asp13 and Asp421 (ref. 30), both of which are cleaved by caspase-3 and caspase-6 (ref. 31). Our in vitro data showed that caspase-2 cleaves recombinant full-length tau preferentially at Asp421. However, in rTg4510 mice we found less Δtau421 than Δtau314, which may be due to steric hindrance caused by an as yet unidentified factor interacting at residues 315-421, which tether tau to the dendritic shaft (X.Z., unpublished data), or to more rapid degradation of Δtau421 (ref. 32). Δtau421 forms fibrils readily in vitro and when expressed in neurons in culture and in mice7, 33. However, the effects of caspase-mediated cleavage of tau at Asp421 on neurons remain unclear, as there are conflicting results (reviewed in ref. 34). In rTg4510 mice caspase activation precedes the appearance of Δtau421 and neurofibrillary tangles, which are associated with the preservation of neurons7, an unexpected result suggesting that cleaving tau at Asp421 may promote neuron survival. Thus, the consequences of tau cleavage by caspase-2 may be more harmful to neuronal function than cleavage by caspase-3 or caspase-6.
In contrast to Δtau421 and other amino-terminal fibrillation-prone tau fragments7, 33, 35, Δtau314 is unique among truncated tau species in that it resists fibrillation. Biophysical studies indicate that a nucleation motif, Asp314-Leu-Ser-Lys-Val-Thr-Ser320, at the beginning of the third microtubule-binding repeat is essential for tau fibrillation36. Our findings are consistent with these studies by providing direct evidence that Δtau314, which is missing six of the seven residues in the motif, resists forming fibrils.
Various proteases unrelated to caspases also cleave tau, but before our studies only one, asparagine endopeptidase (AEP), had been shown to mediate tau-induced synaptic and cognitive dysfunction in mammals35. AEP digests tau after Asn255 and Asn368, and two of the resultant cleavage products, tau(1-368) and tau(256-368), are neurotoxic and prone to fibrillation in vitro.
Although AEP and caspase-2 superficially resemble each other in their effects on tau-mediated synaptotoxicity, there are differences that may be important in determining their ultimate value as drug targets. One relevant distinction is the mechanism underlying memory deficits in PS19 and rTg4510 mice, which were used to study AEP and caspase-2, respectively. In PS19 mice the earliest signs of memory dysfunction correlate with synaptic loss and are probably due to reductions in synapses37, whereas in rTg4510 mice they appear before synaptic density decreases and are most likely caused by synaptic dysfunction10, 11, 12, 13, 15. AEP and caspase-2 may mediate tau-induced synaptic loss and dysfunction, respectively. The current evidence suggests that preventing caspase-2 from cleaving tau could potentially reverse existing deficits and restore cognition, warranting efforts to develop appropriate drugs to inhibit this protease.
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