The prion protein (PrP) is best known for its association with prion diseases. However, a controversial new role for PrP in Alzheimer disease (AD) has recently emerged. In vitro studies and mouse models of AD suggest that PrP may be involved in AD pathogenesis through a highly specific interaction with amyloid-␤ (A␤42) oligomers. Immobilized recombinant human PrP (huPrP) also exhibited high affinity and specificity for A␤42 oligomers. Here we report the novel finding that aggregated forms of huPrP and A␤42 are co-purified from AD brain extracts. Moreover, an anti-PrP antibody and an agent that specifically binds to insoluble PrP (iPrP) co-precipitate insoluble A␤ from human AD brain. Finally, using peptide membrane arrays of 99 13-mer peptides that span the entire sequence of mature huPrP, two distinct types of A␤ binding sites on huPrP are identified in vitro. One specifically binds to A␤42 and the other binds to both A␤42 and A␤40. Notably, A␤42-specific binding sites are localized predominantly in the octapeptide repeat region, whereas sites that bind both A␤40 and A␤42 are mainly in the extreme N-terminal or C-terminal domains of PrP. Our study suggests that iPrP is the major PrP species that interacts with insoluble A␤42 in vivo. Although this work indicated the interaction of A␤42 with huPrP in the AD brain, the pathophysiological relevance of the iPrP/A␤42 interaction remains to be established. Alzheimer disease (AD)2 is the leading cause of dementia in the elderly and the most common neurodegenerative disorder. The underlying pathology in AD seems to be associated with the accumulation of soluble and insoluble aggregated species of the amyloid-␤ (A␤) peptide in the brain (1). However, the mechanisms underlying A␤ deposition and neurotoxicity remain poorly understood. The cellular prion protein (PrP C ) is a glycoprotein highly expressed in the brain, and best known for its association with prion diseases. These are unique neurodegenerative disorders with an infectious, sporadic or genetic etiology, and which are characterized by deposition of misfolded, pathological PrP (PrP Sc ) in the brain (2). Interestingly, a recent interpretation of early and newer observations suggests that PrP C may play a role in the pathogenesis of AD (3). Epidemiological studies suggest that the Met/Val polymorphism at residue 129 in PrP modulates the number of A␤ deposits (4). Also, pathological evidence indicates that PrP deposits often accompany A␤ plaques in AD (5-7). Moreover, transgenic mice expressing mutant amyloid precursor protein (APP) and overexpressing hamster PrP C present an exacerbated A␤ plaque burden (8). The circumstantial evidence of an association between PrP and A␤ was greatly strengthened by the recent finding that PrP was the protein that most strongly supported the binding of cells to soluble A␤42 oligomers in a screen of 225,000 murine clones (9). The authors also showed that although A␤42 oligomers suppressed long-term potentiation (LTP) in CA1 hippocampal neurons in mouse brain slices, LTP inhibitio...

Many different proteins associated with the cell cycle , including cyclins , cyclin-dependent kinases , and proto-oncogenes such as c-MYC (MYC), are increased in degenerating neurons. Consequently, an ectopic activation of the cell cycle machinery in neurons has emerged as a potential pathogenic mechanism of neuronal dysfunction and death in many neurodegenerative diseases, including Alzheimer's disease. However, the exact role of cell cycle re-entry during disease pathogenesis is unclear, primarily because of the lack of relevant research models to study the effects of cell cycle re-entry on mature neurons in vivo. To address this issue, we developed a new transgenic mouse model in which forebrain neurons (CaMKII-MYC) can be induced to enter the cell cycle using the physiologically relevant proto-oncogene MYC to drive cell cycle re-entry. We show that such cell cycle re-entry results in neuronal cell death, gliosis, and cognitive deficits. These findings provide compelling evidence that dysregulation of cell cycle re-entry results in neurodegeneration in vivo. Our current findings , coupled with those of previous reports , strengthen the hypothesis that neurodegeneration in Alzheimer's disease , similar to cellular proliferation in cancer , is a disease that results from inappropriate cell cycle control. (Am J Pathol

J. Neurochem. (2010) 112, 870–881. Abstract Declining levels of estrogen in women result in increases in gonadotropins such as luteinizing hormone (LH) through loss of feedback inhibition. LH, like estrogen, is modulated by hormone replacement therapy. However, the role of post‐menopausal gonadotropin increases on cognition has not been evaluated. Here, we demonstrate that the down‐regulation of ovariectomy‐driven LH elevations using the gonadotropin releasing hormone super‐analogue, leuprolide acetate, improves cognitive function in the Morris water maze and Y‐maze tests in the absence of E2. Furthermore, our data suggest that these effects are independent of the modulation of estrogen receptors α and β, or activation of CYP19 and StAR, associated with the production of endogenous E2. Importantly, pathways associated with improved cognition such as CaMKII and GluR1‐Ser831 are up‐regulated by leuprolide treatment but not by chronic long‐term E2 replacement suggesting independent cognition‐modulating properties. Our findings suggest that down‐regulation of gonadotropins is as effective as E2 in modulating cognition but likely acts through different molecular mechanisms. These findings provide a potential novel protective strategy to treat menopause/age‐related cognitive decline and/or prevent the development of AD.

While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a “fetal re-expression” pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.

Heme is an essential cell metabolite, intracellular regulatory molecule, and protein prosthetic group. Given the known alterations in heme metabolism and redox metal distribution and the up regulation of heme oxygenase enzyme in Alzheimer’s disease (AD), we hypothesized that heme dyshomeostasis plays a key role in the pathogenesis. To begin testing this hypothesis, we used qRT-PCR to quantify the expression of aminolevulinate synthase (ALAS1) and porphobilinogen deaminase (PBGD), rate-limiting enzymes in the heme biosynthesis pathway. The relative expression of ALAS1 mRNA, the first and rate-limiting enzyme for heme biosynthesis under normal physiological conditions, was significantly (p < 0.05) reduced by nearly 90% in AD compared to control. Coordinately, the relative expression of PBGD mRNA, which encodes porphobilinogen deaminase, the third enzyme in the heme synthesis pathway and a secondary rate-limiting enzyme in heme biosynthesis, was also significantly (p < 0.02) reduced by nearly 60% in AD brain compared to control and significantly related to apolipoprotein E genotype (p < 0.005). In contrast, the relative expression of ALAD mRNA, which encodes aminolevulinate dehydratase, the second and a non-rate-limiting enzyme for heme biosynthesis, was unchanged between the two groups. Taken together, our results suggest regulation of cerebral heme biosynthesis is profoundly altered in AD and may contribute toward disease pathogenesis by affecting cell metabolism as well as iron homeostasis.