The NAD-dependent histone deacetylase Sirt1 antagonizes p53 transcriptional activity to regulate cell-cycle progression and apoptosis. We have identified a ubiquitin-specific peptidase, USP22, one of the 11 death-from-cancer signature genes that are critical in controlling cell growth and death, as a positive regulator of Sirt1. USP22 interacts with and stabilizes Sirt1 by removing polyubiquitin chains conjugated onto Sirt1. The USP22-mediated stabilization of Sirt1 leads to decreasing levels of p53 acetylation and suppression of p53-mediated functions. In contrast, depletion of endogenous USP22 by RNA interference destabilizes Sirt1, inhibits Sirt1-mediated deacetylation of p53 and elevates p53-dependent apoptosis. Genetic deletion of the usp22 gene results in Sirt1 instability, elevated p53 transcriptional activity and early embryonic lethality in mice. Our study elucidates a molecular mechanism in suppression of cell apoptosis by stabilizing Sirt1 in response to DNA damage and reveals a critical physiological function of USP22 in mouse embryonic development.

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Aggregation of the amyloid-␤ (A␤) peptide in the extracellular space of the brain is critical in the pathogenesis of Alzheimer's disease. A␤ is produced by neurons and released into the brain interstitial fluid (ISF), a process regulated by synaptic activity. To determine whether behavioral stressors can regulate ISF A␤ levels, we assessed the effects of chronic and acute stress paradigms in amyloid precursor protein transgenic mice. Isolation stress over 3 months increased A␤ levels by 84%. Similarly, acute restraint stress increased A␤ levels over hours. Exogenous corticotropin-releasing factor (CRF) but not corticosterone mimicked the effects of acute restraint stress. Inhibition of endogenous CRF receptors or neuronal activity blocked the effects of acute stress on A␤. Thus, behavioral stressors can rapidly increase ISF A␤ through neuronal activity in a CRF-dependent manner, and the results suggest a mechanism by which behavioral stress may affect Alzheimer's disease pathogenesis.Alzheimer's disease ͉ synaptic activity ͉ environmental stress ͉ microdialysis ͉ transgenic E vidence indicates that the aggregation and accumulation of the amyloid-␤ (A␤) peptide in the brain extracellular space is a key initiating event in the pathogenesis of Alzheimer's disease (AD) (1). A number of studies demonstrate that aggregation of A␤ is concentration-dependent (2). Increasing the amount of A␤ produced by 50% or specifically increasing the more fibrillogenic A␤ 42 either by APP gene dose or mutations in amyloid precursor protein (APP), PS1, or PS2, accelerates the onset of A␤ deposition and AD (3). Conversely, decreasing A␤ by decreasing cleavage of APP or by enhancing clearance of A␤ delays the onset of A␤ deposition (4). Thus, determining factors that regulate the levels of A␤ in the brain extracellular space, where it likely changes conformation and aggregates, may provide insight into AD pathogenesis and treatment.A␤ is produced in the brain primarily by neurons after cleavage of APP by ␤-and ␥-secretase (1). A␤ levels in the extracellular space are then influenced by factors regulating its release from neurons as well as postsecretory events such as transport and clearance. Recent evidence (5, 6) has shown that A␤ release from neurons is regulated by neuronal and specifically synaptic activity over minutes to hours. However, whether behavioral manipulations regulate synaptic activity and interstitial fluid (ISF) A␤ levels has not been addressed.Evidence in both humans and animals suggests that environmental stressors may increase risk for AD or AD pathology. In humans, persons without dementia who are prone to psychological distress are more likely to develop AD (7,8). Also, plasma levels of the stress hormone, cortisol, are correlated with the rate of dementia progression in patients with AD (9). In mouse models of AD, animals subjected to isolation stress over months had decreased learning performance and accelerated A␤ deposition (10). To explore the potential mechanisms and links between behavioral stressors and A...

Clinical studies indicate that Alzheimer's disease (AD) disproportionately affects women in both disease prevalence and rate of symptom progression, but the mechanisms underlying this sexual divergence are unknown. Although some have suggested this difference in risk is a reflection of the known differences in longevity between men and women, mounting clinical and preclinical evidence supports women also having intrinsic susceptibilities toward the disease. Although a number of potential risk factors have been hypothesized to mediate these differences, none have been definitively verified. In this review, we first summarize the epidemiologic studies of prevalence and incidence of AD among the sexes. Next, we discuss the most likely risk factors to date that interact with biological sex, including (1) genetic factors, (2) sex hormones (3) deviations in brain structure, (4) inflammation and microglia, and (5) and psychosocial stress responses. Overall, though differences in life span are likely to account for part of the divide between the sexes in AD prevalence, the abundance of preclinical and clinical evidence presented here suggests an increase in intrinsic AD risk for women. Therefore, future studies focusing on the underlying biological mechanisms for this phenomenon are needed to better understand AD pathogenesis in both sexes, with the eventual goal of sex-specific prevention and treatment strategies.

Higher HPA activity, as reflected by increased plasma cortisol levels, is associated with more rapid disease progression in subjects with Alzheimer-type dementia.