A primary pathologic component of Alzheimer's disease (AD) is the formation of neurofibrillary tangles composed of hyperphosphorylated tau (p-tau). Expediting the removal of these p-tau species may be a relevant therapeutic strategy. Here we report that inhibition of Hsp90 led to decreases in p-tau levels independent of heat shock factor 1 (HSF1) activation. A critical mediator of this mechanism was carboxy terminus of Hsp70-interacting protein (CHIP), a tau ubiquitin ligase. Cochaperones were also involved in Hsp90-mediated removal of p-tau, while those of the mature Hsp90 refolding complex prevented this effect. This is the first demonstration to our knowledge that blockade of the refolding pathway promotes p-tau turnover through degradation. We also show that peripheral administration of a novel Hsp90 inhibitor promoted selective decreases in p-tau species in a mouse model of tauopathy, further suggesting a central role for the Hsp90 complex in the pathogenesis of tauopathies. When taken in the context of known high-affinity Hsp90 complexes in affected regions of the AD brain, these data implicate a central role for Hsp90 in the development of AD and other tauopathies and may provide a rationale for the development of novel Hsp90-based therapeutic strategies.

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We designed a prospective, double-blind controlled trial to determine predictors of loss of renal function in patients with insulin dependent diabetes and established nephropathy. A total of 409 insulin-dependent diabetic patients with established nephropathy enrolled in a trial on the effect of Captopril on the rate of progression of renal disease. Baseline demographic, clinical (history and physical) and laboratory parameters were analyzed as risk factors for time to progression. Dichotomous characteristics were compared by Fisher's exact test and continuous characteristics with the Wilcoxon rank-sum test. Univariate proportional hazards regression analysis was used to estimate relative risk of nephropathy progression, and bivariate proportional hazard regression to identify interactions with the treatment group assignment. Multivariate proportional hazard regression was employed to determine which characteristics were independent risk factors. We found that a number of demographic and clinical characteristics were significantly associated with nephropathy progression even after adjustment for treatment group. However, after multivariate analysis, the risk factors that independently predicted progression were onset of IDDM later in life, parental diagnosis of IDDM, the presence of edema, increased mean arterial pressure, and an abnormal electrocardiogram. Likewise, a number of laboratory characteristics were also predictive of nephropathy progression. A low hematocrit, high blood sugar, and higher protein excretion predicted nephropathy progression as did a higher serum creatinine, particularly in the face of a normal serum albumin. In conclusion, this study identifies a number of clinical and laboratory risk factors that can predict which patients with insulin-dependent diabetes with established nephropathy are more likely to sustain a clinically important decrease in renal function over a median follow-up of three years.

The term "renoprotection" often evokes a single image:Background. Renal disease that progresses to end-stage reangiotensin-converting enzyme (ACE) inhibition therapy nal disease (ESRD) imposes a great burden on the affected to slow the "progression of renal disease." ACE inhibiindividual and on society, which mainly bears the cost of ESRD tors certainly deserve that reputation [1]. Nevertheless, (currently more than $10 billion to treat about 333,000 patients this therapy alone rarely stops renal disease progression.annually in the U.S.). Thus, there is a great need to identify Herein, we describe a multiple-risk-factor intervention therapies that arrest the progression mechanisms common to all forms of renal disease. Progress is being made. Perhaps the strategy based on inhibiting the progression mechanisms most visible advance is the randomized controlled trials (RCT) believed to be common to most forms of progressive demonstrating the renoprotective effects of angiotensin-conrenal disease. To assist the treating physician, each interverting enzyme (ACE) inhibitors. There are also numerous vention is described in substantial practical detail and other promising renoprotective therapies. Unfortunately, testprioritized according to level of recommendation. The ing each therapy in RCT is not feasible. Thus the nephrologist incentive to use the multiple-risk-factor intervention is has two choices: restrict renoprotective therapy to those shown to be effective in RCT, or expand the use of renoprotective that each intervention is either of proven value or plausitherapies to include those that, although unproven, are plausibly effective and prudent to use. Furthermore, renal disbly effective and prudent to use. The goal of this work is ease generally progresses slowly [glomerular filtration to provide the documentation needed for the nephrologist to rate (GFR) loss of about 3 mL/min/year] [2]. Thus, even choose between these strategies. small improvements in slowing renal disease progression Methods. This work first describes the mechanisms believed can provide large benefits (Fig. 1). Our hypothesis is that to be involved in the progression of renal disease. Based largely