Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation.

In Alzheimer's disease (AD), the mechanisms of neuronal loss remain largely unknown. Although tau pathology is closely correlated with neuronal loss, how its accumulation may lead to activation of neurotoxic pathways is unclear. Here we show that tau increased the levels of ubiquitinated proteins in the brain and triggered activation of the unfolded protein response (UPR). This suggested that tau interferes with protein quality control in the endoplasmic reticulum (ER). Consistent with this, ubiquitin was found to associate with the ER in human AD brains and tau transgenic (rTg4510) mouse brains, but this was not always colocalized with tau. The increased levels of ubiquitinated protein were accompanied by increased levels of phosphorylated protein kinase R-like ER kinase (pPERK), a marker that indicates UPR activation. Depleting soluble tau levels in cells and brain could reverse UPR activation. Tau accumulation facilitated its deleterious interaction with ER membrane and associated proteins that are essential for ER-associated degradation (ERAD), including valosin-containing protein (VCP) and Hrd1. Based on this, the effects of tau accumulation on ERAD efficiency were evaluated using the CD3δ reporter, an ERAD substrate. Indeed, CD3δ accumulated in both in vitro and in vivo models of tau overexpression and AD brains. These data suggest that soluble tau impairs ERAD and the result is activation of the UPR. The reversibility of this process, however, suggests that tau-based therapeutics could significantly delay this type of cell death and therefore disease progression.

Evaluation of the C1-C2 articulation on MDCT in healthy children and young adults.

OBJECTIVE: We aimed to establish normal values on MDCT images for the atlantoaxial relationships including the atlantoaxial interval and lateral atlantodens interval (ADI) that could be used to detect atlantoaxial ligamentous injuries in adults and children. MATERIALS AND METHODS: One hundred seventy-eight healthy adult patients between 20 and 40 years old and 112 pediatric patients between 2 months and 10 years old underwent cervical spine MDCT with multiplanar reconstructions. The width of the joint space between the lateral mass of C1 and the lateral mass of C2 was measured at three equidistant points on both the left and right sides on coronal reformatted images to determine the atlantoaxial interval. The distance between the lateral surface of the dens and the medial surface of the lateral mass of C1 was measured in the coronal plane to determine the lateral ADI bilaterally. RESULTS: The upper limit of the normal range of values for the atlantoaxial interval in adults was 3.34 mm on the right and 3.39 mm on the left. The upper limit of normal for the lateral ADI was 4.67 mm on the right and 5.6 mm on the left. More than 95% of the pediatric population was found to have an atlantoaxial interval of less than 3.9 mm on either side, a right lateral ADI of less than 7.4 mm, and a left lateral ADI of less than 8.0 mm. CONCLUSION: We propose that the obtained normal values be considered as the upper limits of the normal range for the atlantoaxial interval in adult and pediatric populations on MDCT images.

Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau.

BACKGROUND: The microtubule-associated protein tau accumulates in neurodegenerative diseases known as tauopathies, the most common being Alzheimer's disease. One way to treat these disorders may be to reduce abnormal tau levels through chaperone manipulation, thus subverting synaptic plasticity defects caused by tau's toxic accretion. METHODS: Tauopathy models were used to study the impact of YM-01 on tau. YM-01 is an allosteric promoter of triage functions of the most abundant variant of the heat shock protein 70 (Hsp70) family in the brain, heat shock cognate 70 protein (Hsc70). The mechanisms by which YM-01 modified Hsc70 activity and tau stability were evaluated with biochemical methods, cell cultures, and primary neuronal cultures from tau transgenic mice. YM-01 was also administered to acute brain slices of tau mice; changes in tau stability and electrophysiological correlates of learning and memory were measured. RESULTS: Tau levels were rapidly and potently reduced in vitro and ex vivo upon treatment with nanomolar concentrations of YM-01. Consistent with Hsc70 having a key role in this process, overexpression of heat shock protein 40 (DNAJB2), an Hsp70 co-chaperone, suppressed YM-01 activity. In contrast to its effects in pathogenic tauopathy models, YM-01 had little activity in ex vivo brain slices from normal, wild-type mice unless microtubules were disrupted, suggesting that Hsc70 acts preferentially on abnormal pools of free tau. Finally, treatment with YM-01 increased long-term potentiation in tau transgenic brain slices. CONCLUSIONS: Therapeutics that exploit the ability of chaperones to selectively target abnormal tau can rapidly and potently rescue the synaptic dysfunction that occurs in Alzheimer's disease and other tauopathies.