Laura Gasparini

Does insulin dysfunction play a role in Alzheimer's disease?

Age-related changes in hormone levels are determinants of a variety of human diseases. Insulin is known to affect numerous brain functions including cognition and memory, and several clinical studies have established links between Alzheimers disease (AD), insulin resistance and diabetes mellitus. These are reinforced by biological studies that reveal the effects of insulin on the molecular and cellular mechanisms that underlie the pathology of AD. For example, insulin regulates phosphorylation of tau protein, which underlies neurofibrillary lesions in the brains of AD patients. Insulin also affects the metabolism of beta-amyloid, the main constituent of AD amyloid pathology. Here, we discuss clinical and biological data that highlight potential targets for therapeutic intervention.

Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription

Epidemiological, clinical and experimental evidence suggests a link between type 2 diabetes and Alzheimers disease (AD). Insulin modulates metabolism of β-amyloid precursor protein (APP) in neurons, decreasing the intracellular accumulation of β-amyloid (Aβ) peptides, which are pivotal in AD pathogenesis. The present study investigates whether the widely prescribed insulin-sensitizing drug, metformin (GlucophageR), affects APP metabolism and Aβ generation in various cell models. We demonstrate that metformin, at doses that lead to activation of the AMP-activated protein kinase (AMPK), significantly increases the generation of both intracellular and extracellular Aβ species. Furthermore, the effect of metformin on Aβ generation is mediated by transcriptional up-regulation of β-secretase (BACE1), which results in an elevated protein level and increased enzymatic activity. Unlike insulin, metformin exerts no effect on Aβ degradation. In addition, we found that glucose deprivation and various tyrphostins, known inhibitors of insulin-like growth factors/insulin receptor tyrosine kinases, do not modulate the effect of metformin on Aβ. Finally, inhibition of AMP-activated protein kinase (AMPK) by the pharmacological inhibitor Compound C largely suppresses metformins effect on Aβ generation and BACE1 transcription, suggesting an AMPK-dependent mechanism. Although insulin and metformin display opposing effects on Aβ generation, in combined use, metformin enhances insulins effect in reducing Aβ levels. Our findings suggest a potentially harmful consequence of this widely prescribed antidiabetic drug when used as a monotherapy in elderly diabetic patients.

Potential roles of insulin and IGF-1 in Alzheimer's disease.

Aging is characterized by a significant decline of metabolic and hormonal functions, which often facilitates the onset of severe age-associated pathologies. One outstanding example of this is the reported association of deranged signaling by insulin and insulin-like-growth-factor 1 (IGF-1) with Alzheimers disease (AD). Recent compelling biological data reveal effects of insulin and IGF-1 on molecular and cellular mechanisms underlying the pathology of AD. This review discusses available biological data that highlight the therapeutic potential of the insulin-IGF-1 signaling pathway in AD.

Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease: old and new mechanisms of action

Alzheimers disease (AD) is characterized by cerebral deposits of β‐amyloid (Aβ) peptides and neurofibrillary tangles (NFT) which are surrounded by inflammatory cells. Epidemiological studies have shown that prolonged use of non‐steroidal anti‐inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays the onset of the disease. It has been postulated that some NSAIDs target pathological hallmarks of AD by interacting with several pathways, including the inhibition of cyclooxygenases (COX) and activation of the peroxisome proliferator‐activated receptor γ. A variety of experimental studies indicate that a subset of NSAIDs such as ibuprofen, flurbiprofen, indomethacin and sulindac also possess Aβ‐lowering properties in both AD transgenic mice and cell cultures of peripheral, glial and neuronal origin. While COX inhibition occurs at low concentrations in vitro (nM‐low μm range), the Aβ‐lowering activity is observed at high concentrations (≤ 50 μm). Nonetheless, studies with flurbiprofen or ibuprofen in AD transgenic mice show that the effects on Aβ levels or deposition are attained at plasma levels similar to those achieved in humans at therapeutic dosage. Still, it remains to be assessed whether adequate concentrations are reached in the brain. This is a crucial aspect that will allow defining the dose‐window and the length of treatment in future clinical trials. Here, we will discuss how the combination of anti‐amyloidogenic and anti‐inflammatory activities of certain NSAIDs may produce a profile potentially relevant to their clinical use as disease‐modifying agents for the treatment of AD.

Interaction of tau protein with the dynactin complex

Tau is an axonal microtubule‐associated protein involved in microtubule assembly and stabilization. Mutations in Tau cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17), and tau aggregates are present in Alzheimers disease and other tauopathies. The mechanisms leading from tau dysfunction to neurodegeneration are still debated. The dynein–activator complex dynactin has an essential role in axonal transport and mutations in its gene are associated with lower motor neuron disease. We show here for the first time that the N‐terminal projection domain of tau binds to the C‐terminus of the p150 subunit of the dynactin complex. Tau and dynactin show extensive colocalization, and the attachment of the dynactin complex to microtubules is enhanced by tau. Mutations of a conserved arginine residue in the N‐terminus of tau, found in patients with FTDP‐17, affect its binding to dynactin, which is abnormally distributed in the retinal ganglion cell axons of transgenic mice expressing human tau with a mutation in the microtubule‐binding domain. These findings, which suggest a direct involvement of tau in axonal transport, have implications for understanding the pathogenesis of tauopathies.

Modulation of β‐amyloid metabolism by non‐steroidal anti‐inflammatory drugs in neuronal cell cultures

Alzheimer disease (AD) is characterized by cerebral deposits of β‐amyloid (Aβ) peptides, which are surrounded by neuroinflammatory cells. Epidemiological studies have shown that prolonged use of non‐steroidal anti‐inflammatory drugs (NSAIDs) reduces the risk of developing AD. In addition, biological data indicate that certain NSAIDs specifically lower Aβ42 levels in cultures of peripheral cells independently of cyclooxygenase (COX) activity and reduce cerebral Aβ levels in AD transgenic mice. Whether other NSAIDs, including COX‐selective compounds, modulate Aβ levels in neuronal cells remains unexploited. Here, we investigated the effects of compounds from every chemical class of NSAIDs on Aβ40 and Aβ42 secretion using both Neuro‐2a cells and rat primary cortical neurons. Among non‐selective NSAIDs, flurbiprofen and sulindac sulfide concentration‐dependently reduced the secretion not only of Aβ42 but also of Aβ40. Surprisingly, both COX‐2 (celecoxib; sc‐125) or COX‐1 (sc‐560) selective compounds significantly increased Aβ42 secretion, and either did not alter (sc‐560; sc‐125) or reduced (celecoxib) Aβ40 levels. The levels of βAPP C‐terminal fragments and Notch cleavage were not altered by any of the NSAIDs, indicating that γ‐secretase activity was not overall changed by these drugs. The present findings show that only a few non‐selective NSAIDs possess Aβ‐lowering properties and therefore have a profile potentially relevant to their clinical use in AD.

Communication breaks-Down: From neurodevelopment defects to cognitive disabilities in Down syndrome

Down syndrome (DS) is the leading cause of genetically-defined intellectual disability and congenital birth defects. Despite being one of the first genetic diseases identified, only recently, thanks to the phenotypic analysis of DS mouse genetic models, we have begun to understand how trisomy may impact cognitive function. Cognitive disabilities in DS appear to result mainly from two pathological processes: neurogenesis impairment and Alzheimer-like degeneration. In DS brain, suboptimal network architecture and altered synaptic communication arising from neurodevelopmental impairment are key determinants of cognitive defects. Hypocellularity and hypoplasia start at early developmental stages and likely depend upon impaired proliferation of neuronal precursors, resulting in reduction of numbers of neurons and synaptic contacts. The impairment of neuronal precursor proliferation extends to adult neurogenesis and may affect learning and memory. Neurodegenerative mechanisms also contribute to DS cognitive impairment. Early onset Alzheimer disease occurs with extremely high incidence in DS patients and is causally-related to overexpression of beta-amyloid precursor protein (betaAPP), which is one of the triplicated genes in DS. In this review, we will survey the available findings on neurodevelopmental and neurodegenerative changes occurring in DS throughout life. Moreover, we will discuss the potential mechanisms by which defects in neurogenesis and neurodegenerative processes lead to altered formation of neural circuits and impair cognitive function, in connection with findings on pharmacological treatments of potential benefit for DS.

Lithium rescues synaptic plasticity and memory in Down syndrome mice

Down syndrome (DS) patients exhibit abnormalities of hippocampal-dependent explicit memory, a feature that is replicated in relevant mouse models of the disease. Adult hippocampal neurogenesis, which is impaired in DS and other neuropsychiatric diseases, plays a key role in hippocampal circuit plasticity and has been implicated in learning and memory. However, it remains unknown whether increasing adult neurogenesis improves hippocampal plasticity and behavioral performance in the multifactorial context of DS. We report that, in the Ts65Dn mouse model of DS, chronic administration of lithium, a clinically used mood stabilizer, promoted the proliferation of neuronal precursor cells through the pharmacological activation of the Wnt/β-catenin pathway and restored adult neurogenesis in the hippocampal dentate gyrus (DG) to physiological levels. The restoration of adult neurogenesis completely rescued the synaptic plasticity of newborn neurons in the DG and led to the full recovery of behavioral performance in fear conditioning, object location, and novel object recognition tests. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult DS mice rescues hippocampal plasticity and memory and implicate adult neurogenesis as a promising therapeutic target to alleviate cognitive deficits in DS patients.

Attenuation of chronic neuroinflammation by a nitric oxide-releasing derivative of the antioxidant ferulic acid

Chronic neuroinflammation and oxidative stress contribute to the neurodegeneration associated with Alzheimers disease and represent targets for therapy. Ferulic acid is a natural compound that expresses antioxidant and anti‐inflammatory activities. Nitric oxide is also a key modulator of inflammatory responses. Grafting a nitric oxide‐releasing moiety onto anti‐inflammatory drugs results in enhanced anti‐inflammatory activity. We compared the effectiveness of ferulic acid with a novel nitric oxide‐releasing derivative of ferulic acid in an animal model of chronic neuroinflammation that reproduces many interesting features of Alzheimers disease. Lipopolysaccharide was infused into the 4th ventricle of young rats for 14 days. Various doses of ferulic acid or its nitric oxide‐releasing derivative were administered daily. Both drugs produced a dose‐dependent reduction in microglia activation within the temporal lobe. However, the nitric oxide‐releasing ferulic acid derivative was significantly more potent. If we delayed the initiation of therapy for 14 days, we found no reduction in microglial activation. In addition, both drugs demonstrated antioxidant and hydroxyl radical scavenging abilities in in vitro studies. Overall, our results predict that a treatment using nitric oxide‐releasing ferulic acid may attenuate the processes that drive the pathology associated with Alzheimers disease if the treatment is initiated before the neuroinflammatory processes can develop.

Presenilin 1 Protein Directly Interacts with Bcl-2

Presenilin proteins are involved in familial Alzheimers disease, a neurodegenerative disorder characterized by massive death of neurons. We describe a direct interaction between presenilin 1 (PS1) and Bcl-2, a key factor in the regulation of apoptosis, by yeast two-hybrid interaction system, by co-immunoprecipitation, and by cross-linking experiments. Our data show that PS1 and Bcl-2 assemble into a macromolecular complex, and that they are released from this complex in response to an apoptotic stimulus induced by staurosporine. The results support the idea of cross-talk between these two proteins during apoptosis.