Lucia Privitera

Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus.

Amyloid-β (Aβ) peptides are produced in high amounts during Alzheimers disease, causing synaptic and memory dysfunction. However, they are also released in lower amounts in normal brains throughout life during synaptic activity. Here we show that low picomolar concentrations of a preparation containing both Aβ42 monomers and oligomers cause a marked increase of hippocampal long-term potentiation, whereas high nanomolar concentrations lead to the well established reduction of potentiation. Picomolar levels of Aβ42 also produce a pronounced enhancement of both reference and contextual fear memory. The mechanism of action of picomolar Aβ42 on both synaptic plasticity and memory involves α7-containing nicotinic acetylcholine receptors. These findings strongly support a model for Aβ effects in which low concentrations play a novel positive, modulatory role on neurotransmission and memory, whereas high concentrations play the well known detrimental effect culminating in dementia.

Phosphodiesterase 5 Inhibition Improves Synaptic Function, Memory, and Amyloid-β Load in an Alzheimer's Disease Mouse Model

Memory loss, synaptic dysfunction, and accumulation of amyloid β-peptides (Aβ) are major hallmarks of Alzheimers disease (AD). Downregulation of the nitric oxide/cGMP/cGMP-dependent protein kinase/c-AMP responsive element-binding protein (CREB) cascade has been linked to the synaptic deficits after Aβ elevation. Here, we report that the phosphodiesterase 5 inhibitor (PDE5) sildenafil (Viagra), a molecule that enhances phosphorylation of CREB, a molecule involved in memory, through elevation of cGMP levels, is beneficial against the AD phenotype in a mouse model of amyloid deposition. We demonstrate that the inhibitor produces an immediate and long-lasting amelioration of synaptic function, CREB phosphorylation, and memory. This effect is also associated with a long-lasting reduction of Aβ levels. Given that side effects of PDE5 inhibitors are widely known and do not preclude their administration to a senile population, these drugs have potential for the treatment of AD and other diseases associated with elevated Aβ levels.

Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory

The goal of this study was to investigate the role of endogenous amyloid‐β peptide (Aβ) in healthy brain.

Improved Long-Term Memory via Enhancing cGMP-PKG Signaling Requires cAMP-PKA Signaling

Memory consolidation is defined by the stabilization of a memory trace after acquisition, and consists of numerous molecular cascades that mediate synaptic plasticity. Commonly, a distinction is made between an early and a late consolidation phase, in which early refers to the first hours in which labile synaptic changes occur, whereas late consolidation relates to stable and long-lasting synaptic changes induced by de novo protein synthesis. How these phases are linked at a molecular level is not yet clear. Here we studied the interaction of the cyclic nucleotide-mediated pathways during the different phases of memory consolidation in rodents. In addition, the same pathways were studied in a model of neuronal plasticity, long-term potentiation (LTP). We demonstrated that cGMP/protein kinase G (PKG) signaling mediates early memory consolidation as well as early-phase LTP, whereas cAMP/protein kinase A (PKA) signaling mediates late consolidation and late-phase-like LTP. In addition, we show for the first time that early-phase cGMP/PKG signaling requires late-phase cAMP/PKA-signaling in both LTP and long-term memory formation.

Inhibition of phosphodiesterase-5 rescues age-related impairment of synaptic plasticity and memory

Aging is characterized by a progressive cognitive decline that leads to memory impairment. Because the cyclic nucleotide cascade is essential for the integrity of synaptic function and memory, and it is down-regulated during aging and in neurodegenerative disorders, we investigated whether an increase in cGMP levels might rescue age-related synaptic and memory deficits in mice. We demonstrated that acute perfusion with the phosphodiesterase-5 inhibitor sildenafil (50 nM) ameliorated long-term potentiation in hippocampal slices from 26-30-month-old mice. Moreover, chronic intraperitoneal injection of sildenafil (3mg/kg for 3 weeks) improved age-related spatial learning and reference memory as tested by the Morris Water Maze, and recognition memory as tested by the Object Recognition Test. Finally, sildenafil restored central cAMP responsive element-binding protein (CREB) phosphorylation, which is crucial for synaptic plasticity and memory. Our data suggest that inhibition of phosphodiesterase-5 may be beneficial to treat age-related cognitive dysfunction in a physiological mouse model of aging.

F3/Contactin promotes hippocampal neurogenesis, synaptic plasticity, and memory in adult mice.

F3/contactin, a cell‐adhesion molecule belonging to the immunoglobulin supergene family, is involved in several aspects of neural development including synapse building, maintenance and functioning. Here, we examine F3/contactin function in adult hippocampal neurogenesis, synaptic plasticity, and memory, using as a model TAG/F3 transgenic mice, where F3/contactin overexpression was induced under control of regulatory sequences from the human TAG‐1 (TAX‐1) gene. Transgenic mice aged 5 (M5) and 12 (M12) months exhibited an increase in hippocampal size, which correlated with positive effects on precursor proliferation and NeuN expression, these data suggesting a possible role for F3/contactin in promoting adult hippocampal neurogenesis. On the functional level, TAG/F3 mice exhibited increased CA1 long‐term potentiation and improved spatial and object recognition memory, notably at 12 months of age. Interestingly, these mice showed an increased expression of the phosphorylated transcription factor CREB, which may represent the main molecular correlate of the observed morphological and functional effects. Altogether, these findings indicate for the first time that F3/contactin plays a role in promoting adult hippocampal neurogenesis and that this effect correlates with improved synaptic function and memory.

A novel mechanism for cyclic adenosine monophosphate-mediated memory formation: Role of amyloid beta.

Cyclic adenosine monophosphate (cAMP) regulates long‐term potentiation (LTP) and ameliorates memory in healthy and diseased brain. Increasing evidence shows that, under physiological conditions, low concentrations of amyloid β (Aβ) are necessary for LTP expression and memory formation. Here, we report that cAMP controls amyloid precursor protein (APP) translation and Aβ levels, and that the modulatory effects of cAMP on LTP occur through the stimulation of APP synthesis and Aβ production. Ann Neurol 2014;75:602–607

Neutralization of TNFSF10 ameliorates functional outcome in a murine model of Alzheimer’s disease

Alzheimers disease is one of the most common causes of death worldwide, with poor treatment options. A tissue landmark of Alzheimers disease is accumulation of the anomalous protein amyloid-β in specific brain areas. Whether inflammation is an effect of amyloid-β on the Alzheimers disease brain, or rather it represents a cause for formation of amyloid plaques and intracellular tangles remains a subject of debate. TNFSF10, a proapoptotic cytokine of the TNF superfamily, is a mediator of amyloid-β neurotoxicity. Here, we demonstrate that blocking TNFSF10 by administration of a neutralizing monoclonal antibody could attenuate the amyloid-β-induced neurotoxicity in a triple transgenic mouse model of Alzheimers disease (3xTg-AD). The effects of TNFSF10 neutralization on either cognitive parameters, as well as on the expression of TNFSF10, amyloid-β, inflammatory mediators and GFAP were studied in the hippocampus of 3xTg-AD mice. Treatment with the TNFSF10 neutralizing antibody resulted in dramatic improvement of cognitive parameters, as assessed by the Morris water maze test and the novel object recognition test. These results were correlated with decreased protein expression of TNFSF10, amyloid-β, inflammatory mediators and GFAP in the hippocampus. Finally, neutralization of TNFSF10 results in functional improvement and restrained immune/inflammatory response in the brain of 3xTg-AD mice in vivo. Thus, it is plausible to regard the TNFSF10 system as a potential target for efficacious treatment of amyloid-related disorders.

A PHYSIOLOGICAL ROLE FOR AMYLOID BETA IN CYCLIC AMP-STIMULATED LONG TERM POTENTIATION

phosphorylation of amyloid precursor protein (APP). When phosphorylated at threonine 668 (T668), APP undergoes conformational changes affecting its intracellular sorting and trafficking, which in turns impact proteolytic cleavage and increases A b production. The role of APP T668 phosphorylation and obesity in AD are not well understood and indicate a critical need to understand the mechanism(s) linking obesity and cognitive decline. Methods: Obesity is induced in C57Bl/6 mice using a high fat diet (54% kCal from fat) for 24 wk. APP and tau phosphorylation is examined from cortex lysates. Cortical neurons are prepared from E15 rat embryo and cultured in vitro for 7 days before insulin and/or IGF-I treatment.Results:Obese mice displayed significant cognitive impairment at 24 wk in parallel with the increased tau and T668-APP phosphorylation in the cortex. We previously reported that embryonic cortical neurons (eCN) develop neuronal IR with decreased insulin and IGF-I signaling following chronic insulin treatment. IGF-I treatment of eCN decreased T668-APP phosphorylation. Insulin also decreased APP phosphorylation but the effect was much weaker compared to IGF-I. Chronic treatment of eCN with insulin increased basal T668-APP phosphorylation. IGF-I was still able to reduce T668 phosphorylation after chronic insulin treatment; insulin itself was unable to reduce APP phosphorylation. These effect was reversed with the simultaneous treatment of chronic insulin with PI3-K inhibitor, suggesting chronic hyperactivation of Akt is responsible for IR-induced APP phosphorylation. Conclusions: Our results suggest IR-induced increases in T668 phosphorylation of APP as a possible link between obesity and cognitive impairment. Furthermore our data reveal a potential and beneficial effect of IGF-I signaling as a therapeutic target. This work is supported by the Program for Neurology Research and Discovery (www.med.umich. edu/PNRD).

Amyloid-beta peptide is required for synaptic plasticity and memory

conditions of both diseases, and characterized their phenotypes longitudinally. Methods: We cross-bred amyloid precursor protein transgenic mice (APP-Tg) with two types of diabetes model mice, ob/ob and NSY mouse. APP-Tg crossed with ob/ob mouse was fed normal chow. APP-Tg crossed with NSY mouse was divided into three diet groups, and fed high-fat diet, high-sucrose diet and normal chow. We characterized metabolic phenotypes (body weight, blood glucose and insulin levels, glucose and insulin tolerance) and AD-pathology (cognitive function and brain Ab load) of these model animals longitudinally. Results: Two types of transgenic mice (APP-ob/ob and APP-NSY mouse) with pathological conditions of both diabetes and AD were successfully generated. Compared with APP-Tg, APPob/ob mice gained more body weight and developed marked hyperglycemia, hyperinsulinemia and glucose intolerance. These metabolic changes were associated with the very early (at the age of 2 months) manifestation of memory impairment. Surprisingly, this exacerbation of memory impairment was not accompanied by an increase in the Ab protein levels in the brain compared with APP-Tg. Furthermore, APP-ob/ob mice showed more prominent metabolic dysregulation compared with ob/ob mice. APP-NSY mice also showed early manifestation of cognitive dysfunction at the age of 3-month, without detectable amyloid plaques in the brain. Moreover, 5-month high-calorie feeding induced further exacerbation of memory impairment. Conclusions: We successfully generated two types of novel transgenic mouse models which show pathological phenotypes both of diabetes and AD. Exacerbation of memory impairment without an increase in Ab load in the brain of these diabetic APP-Tg implies the role of diabetic conditions on Ab-mediated neuronal dysfunction. Early manifestation of AD-like cognitive dysfunction of these animals provides a valuable model for drug development or screening for AD. Our findings also suggest the possibility that AD pathology could exacerbate metabolic phenotypes of diabetes.