Type 2 diabetes mellitus (DM) and AlzheimerÕs disease (AD) share epidemiological and biochemical features. Both are characterized by insoluble protein aggregates with a fibrillar conformation -amylin in Type 2 DM pancreatic islets, and Ab in AD brain. To determine whether amylin shares neurotoxic properties with Ab, we incubated hippocampal and cortical neurons with Ab42 and human amylin. Different from non-amyloidogenic rat amylin, both caused a dose-, time-and cell type-specific neurotoxicity supporting the notion of a similar toxic mechanism. Depending on the cell type, this finding is also supported by co-incubation of human amylin and Ab.

SUMMARYIncreased serum levels of interferon-c (IFN-c) have been observed in acute graft-versus-host disease (GVHD). Recent in vitro studies have demonstrated that interleukin-12 (IL-12) and interleukin-18 (IL-18) synergistically up-regulate IFN-c secretion. In this communication, we investigated the factors relevant to IFN-c secretion in acute GVHD. A murine model of acute GVHD was established by injecting donor spleen cells into severe combined immunode®ciency (SCID) mice. A series of specimens, including sera, livers and spleens derived from the GVHD mice, were investigated with histological examination, enzyme-linked immunosorbent assay (ELISA),¯ow cytometry, and semiquantitative reverse transcription±polymerase chain reaction (RT±PCR). IFNc secretion increased in serum 3 days after spleen cell transfer, peaked on day 7, and then gradually decreased close to the baseline level by day 35. A synchronized increase of activated T cells and mRNA expression of IL-12, IL-18 and their respective receptors was observed after spleen cell transfer. However, only the kinetic expression pattern of IL-12 receptor (IL-12R) b2 chains was closely correlated with that of IFN-c, while IL-12 dropped to the baseline level earlier than IFN-c. Therefore, IFN-c expression in the early phase of acute GVHD is a mono-peak and self-restricted pattern. Its secretion is closely related with T-cell activation, the presence of IL-12, IL-18 and their respective receptors. However, the limiting factors for IFN-c secretion seem to be IL-12 and IL-12R b2 chains.

Hormonal deficit in post-menopausal women has been proposed to be one risk factor in Alzheimer's disease (AD) since two thirds of AD patients are women. However, large treatment trials showed negative effects of long-term treatment with oestrogens in older women. Thus, oestrogen treatment after menopause is still under debate, and several hypotheses trying to explain the failure in outcome are under discussion. Concurrently, it was shown that amyloid-beta (Aβ) peptide, the main constituent of senile plaques, as well as abnormally hyperphosphorylated tau protein, the main component of neurofibrillary tangles, can modulate the level of neurosteroids which notably represent neuroactive steroids synthetized within the nervous system, independently of peripheral endocrine glands. In this review, we summarize the role of neurosteroids especially that of oestrogen in AD and discuss their potentially neuroprotective effects with specific regard to the role of oestrogens on the maintenance and function of mitochondria, important organelles which are highly vulnerable to Aβ-and tau-induced toxicity. We also discuss the role of Aβ-binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme able to bind Aβ peptide thereby modifying mitochondrial function as well as oestradiol levels suggesting possible modes of interaction between the three, and the potential therapeutic implication of inhibiting Aβ-ABAD interaction.

Despite extensive research, treatments for clinical stroke are still limited only to the administration of tissue plasminogen activator and the recent introduction of mechanical thrombectomy, which can be used in only a limited proportion of patients due to time constraints. A plethora of inflammatory events occur during stroke, arising in part due to the body’s immune response to brain injury. Neuroinflammation contributes significantly to neuronal cell death and the development of functional impairment and death in stroke patients. Therefore, elucidating the molecular and cellular mechanisms underlying inflammatory damage following stroke injury will be essential for the development of useful therapies. Research findings increasingly point to the likelihood that epigenetic mechanisms play a role in the pathophysiology of stroke. Epigenetics involves the differential regulation of gene expression, including those involved in brain inflammation and remodelling after stroke. Hence, it is conceivable that epigenetic mechanisms may contribute to differential interindividual vulnerability and injury responses to cerebral ischaemia. In this review, we summarize recent findings on the emerging role of epigenetics in the regulation of neuroinflammation in stroke. We also discuss potential epigenetic targets that may be assessed for the development of stroke therapies.

SummaryOxidative damage is associated with Alzheimer's disease and mild cognitive impairment, but its relationship to the development of neuropathological lesions involving accumulation of amyloid-β β β β (Aβ β β β ) peptides and hyperphosphorylated tau protein remains poorly understood. We show that inducing oxidative stress in primary chick brain neurons by exposure to sublethal doses of H 2 O 2 increases levels of total secreted endogenous Aβ β β β by 2.4-fold after 20 h. This occurs in the absence of changes to intracellular amyloid precursor protein or tau protein levels, while heatshock protein 90 is elevated 2.5-fold. These results are consistent with the hypothesis that aging-associated oxidative stress contributes to increasing Aβ β β β generation and upregulation of molecular chaperones in Alzheimer's disease. Key words: Alzheimer's disease; amyloid-β β β β peptide; oxidative stress.Extracellular plaques containing aggregated amyloid-β (A β ) peptides and intracellular neurofibrillary tangles of hyperphosphorylated tau protein are the two salient pathological hallmarks of the Alzheimer's disease (AD) brain. A β is generated by consecutive cleavages of amyloid precursor protein (APP) by β -secretase ( β -site APP cleaving enzyme 1, BACE 1) and the γ -secretase protein complex of which presenilin is the catalytic subunit (Hardy, 2006). Familial mutations in APP or presenilin lead to increased generation and/or aggregation of A β peptides and cause early-onset AD (Hardy, 2006). Aggregated A β interferes with synaptic plasticity and causes neuronal cell death (Lambert et al ., 1998;Townsend et al. , 2006;Kayed et al ., 2004;Wogulis et al ., 2005). This and other evidence supports the amyloid hypothesis which postulates that toxicity exerted by aggregated A β initiates AD, with synaptic dysfunction, neurofibrillary pathology and oxidative injury constituting downstream events (Hardy, 2006). A number of studies, however, suggest that oxidative damage occurs in mild cognitive impairment (MCI) and early stages of sporadic AD, before widespread plaque and tangle development (Sayre et al ., 1997;Butterfield et al ., 2006;Nunomura et al ., 2006;Williams et al ., 2006;Lovell & Markesbery, 2008). Stress-activated BACE 1 and γ -secretase have been proposed to contribute to the deposition of A β peptides in sporadic AD (Tamagno et al ., 2008). Supporting this idea, expression and activity of BACE 1 is elevated in the brains of sporadic AD patients (Fukumoto et al ., 2002;Holsinger et al ., 2002 (Wen et al ., 2004;Tesco et al ., 2007), all of which are events associated with increased sporadic AD risk. These findings suggest that oxidative stress is upstream of A β in AD and that A β might be generated as a compensatory response in neurons attempting to attenuate oxidative stress (Smith et al ., 2002;Lee et al ., 2006). In addition, neurofibrillary degeneration may exacerbate the oxidative damage and elevation of A β (Yan et al ., 1995). In this context, mutations in APP that cause familial AD or in tau that cause fro...