SFRP-mediated Wnt sequestration as a potential therapeutic target for Alzheimer's disease

The extracellular ligand, Wnt, and its receptors are involved in sign al transduction and play an important role in axis formation and neural development. In neurodegenerative disorders such as Alzheimer's disease (AD), a decrease of the intracellular Wnt effector, ß-catenin, has been linked to amyloid-ß-peptide-induced neurotoxicity. Despite this knowledge, targeting Wnt inhibitors as potential biomarkers has not been explored, and harnessing Wnt activators as therapeutic candidates remains largely not investigated. A wide acting family of Wnt mediators, secreted frizzled-related proteins (sFRPs), has not been probed so far as molecular indicators of disease occurrence and progression of Alzheimer's. Unlike the effect of the Dickkopf (DKK) family of Wnt antagonists on AD, the sFRP molecules have a more pleiotropic impact on the Wnt signaling cascade and probably have a far-reaching involvement in neurodegeneration. The role of sFRPs has been poorly described in AD, and in this review, we analyze the present status of the role of sFRPs on neurodegeneration, their likely involvement, and potential implications in treatment modalities of AD. This information would provide valuable clues for the development of potential therapeutic targets for aberrant neurodegenerative disorders

Autophagic activity in neuronal cell death.

As post-mitotic cells with great energy demands, neurons depend upon the homeostatic and waste-recycling functions provided by autophagy. In addition, autophagy also promotes survival during periods of harsh stress and targets aggregate-prone proteins associated with neurodegeneration for degradation. Despite this, autophagy has also been controversially described as a mechanism of programmed cell death. Instances of autophagic cell death are typically associated with elevated numbers of cytoplasmic autophagosomes, which have been assumed to lead to excessive degradation of cellular components. Due to the high activity and reliance on autophagy in neurons, these cells may be particularly susceptible to autophagic death. In this review, we summarize and assess current evidence in support of autophagic cell death in neurons, as well as how the dysregulation of autophagy commonly seen in neurodegeneration can contribute to neuron loss. From here, we discuss potential treatment strategies relevant to such cell-death pathways.DCR is funded by a Wellcome Trust Principal Research Fellowship and the NIHR Biomedical Research Unit in Dementia at Addenbrooke’s Hospital. This review is supported by Plymouth University and Northcott Medical Foundation.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s12264-015-1528-

Mechanisms of amyloid-beta cytotoxicity in hippocampal network function : rescue strategies in Alzheimer's disease

The origin and nature of cognitive processes are strongly associated with synchronous rhythmic activity in the brain. Gamma oscillations that span the frequency range of 30–80 Hz are particularly important for sensory perception, attention, learning, and memory. These oscillations occur intrinsically in brain regions, such as the hippocampus, that are directly linked to memory and disease. It has been reported that gamma and other rhythms are impaired in brain disorders such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia; however, little is known about how these oscillations are affected. In the studies contained in this thesis, we investigated a possible involvement of toxic Amyloid-beta (Aβ) peptide associated with Alzheimer’s disease in degradation of gamma oscillations and the underlying cellular mechanismsin rodent hippocampi. We also aimed to prevent possible Aβ- induced effects by using specially designed molecular tools known to reduce toxicity associated with Aβ by interfering with its folding and aggregation steps. Using electrophysiological techniques to study thelocal field potentials and cellular properties in the CA3 region of the hippocampus, we found that Aβ in physiological concentrations acutely degrades pharmacologically- induced hippocampal gamma oscillations in vitro in a concentration- and time- dependent manner. The severity of degradation also increased with the amount of fibrillar Aβ present. We report that the underlying cause of degradation of gamma oscillations is Aβ-induced desynchronization of action potentials in pyramidal neurons and a shift in the equilibrium of excitatory-inhibitory synaptic transmission. Using specially designed molecular tools such as Aβ-binding ligands and molecular chaperones, we provide evidence that Aβ-induced effects on gamma oscillations, cellular firing, and synaptic dynamics can be prevented. We also show unpublished data on Aβ effects on parvalbumin-positive baskets cells or fast-spiking interneurons, in which Aβ causes an increase in firing rate during gamma oscillations. This is similar to what is observed in neighboring pyramidal neurons, suggesting a general mechanism behind the effect of Aβ. The studies in this thesis provide a correlative link between Aβ-induced effects on excitatory and inhibitory neurons in the hippocampus and extracellular gamma oscillations, and identify the Aβ aggregation state responsible for its toxicity. We demonstrate that strategies aimed at preventing peptide aggregation are able to prevent the toxic effects of Aβ on neurons and gamma oscillations. The studies have the potential to contribute to the design of future therapeutic interventions that are aimed at preserving neuronal oscillations in the brain to achieve cognitive benefits for patients

Regulated protein aggregation: how it takes TIA1 to tangle

The eukaryotic stress response involves translational suppression of non-housekeeping proteins, and the sequestration of unnecessary mRNA transcripts into stress granules (SGs). This process is dependent on mRNA binding proteins (RBPs), such as T- cell intracellular antigen (TIA-1). RBPs interact with unnecessary mRNA transcripts through prion and poly-glutamine like domains, and their aggregation mirrors proteins linked to neurodegenerative diseases. Recent advances in molecular genetics emphasize the importance of SG biology in disease by associating multiple RBPs linked to SGs with neurodegenerative disease. The major difference between SG proteins and aggregation prone proteins in neurodegeneration is that aggregation of SGs is transient and rapidly reverses when the stress is removed. In contrast, aggregates associated with disease are stable and accumulate over time. This study identifies overabundant SGs as a novel pathology in Alzheimer's disease and related tauopathies. The data suggest that TIA-1 is intimately linked to tau pathogenesis, acting as a modifier of tau aggregation and associated toxicity. TIA-1 is present in a protein complex with tau protein including hyper-phosphorylated and misfolded tau. The expression of WT or P301L mutant tau increases the formation and size of TIA-1 positive SGs, and the localization and dynamics of these SGs are altered. Conversely, the expression of TIA-1 increases the formation and stabilization of phospho- and misfolded tau inclusions, as well as visible alterations in microtubule morphology, perhaps reflecting a loss of tau function. The data further show that co-expression of TIA-1 and tau leads to dendrite shortening, increases in caspase cleavage, and apoptosis in primary neurons, suggesting that an interaction between TIA-1 and tau results in neurotoxicity. This toxicity is SG-dependent and is rescued by microtubule stabilizing drugs. The results of this thesis research suggest that the aggregation of tau may proceed through the SG pathway, with SG formation accelerating the pathophysiology of tau aggregation. These studies propose that these tau aggregates serve as a nidus for further accelerated aggregation of SGs, leading to formation of long-lived pathological SG

Chronic Traumatic Encephalopathy-Integration of Canonical Traumatic Brain Injury Secondary Injury Mechanisms with Tau Pathology

In recent years, a new neurodegenerative tauopathy labeled Chronic Traumatic Encephalopathy (CTE), has been identified that is believed to be primarily a sequela of repeated mild traumatic brain injury (TBI), often referred to as concussion, that occurs in athletes participating in contact sports (e.g. boxing, football, football, rugby, soccer, ice hockey) or in military combatants, especially after blast-induced injuries. Since the identification of CTE, and its neuropathological finding of deposits of hyperphosphorylated tau protein, mechanistic attention has been on lumping the disorder together with various other non-traumatic neurodegenerative tauopathies. Indeed, brains from suspected CTE cases that have come to autopsy have been confirmed to have deposits of hyperphosphorylated tau in locations that make its anatomical distribution distinct for other tauopathies. The fact that these individuals experienced repetitive TBI episodes during their athletic or military careers suggests that the secondary injury mechanisms that have been extensively characterized in acute TBI preclinical models, and in TBI patients, including glutamate excitotoxicity, intracellular calcium overload, mitochondrial dysfunction, free radical-induced oxidative damage and neuroinflammation, may contribute to the brain damage associated with CTE. Thus, the current review begins with an in depth analysis of what is known about the tau protein and its functions and dysfunctions followed by a discussion of the major TBI secondary injury mechanisms, and how the latter have been shown to contribute to tau pathology. The value of this review is that it might lead to improved neuroprotective strategies for either prophylactically attenuating the development of CTE or slowing its progression

Glial cells and neuronal function in Alzheimer's disease

In this thesis, we investigated the impact of Alzheimer’s disease on neuronal function and glial cells. Hereto we used various models, i.e. the APPswePS1dE9 AD mouse model, human post-mortem brain material, and a microglia-like cell model. In a review we focused on the role of reactive astrocytes in the AD mouse model, indicating that reactive astrocytes can be a promising treatment target in AD. Using the same mouse model, we investigated changes in neuronal function at various ages. We concluded that aging has a more prominent effect on the measurements than the increased presence of amyloid. In a first experiment, to investigate the potential role of microglia in AD, we used a microglia-like model to examine the effect of Aβ1-42 oligomers on transcriptomic changes. Interestingly, we observed a distinct upregulation of metallothionein subtypes in the Aβ1-42 oligomer stimulated cells. The upregulation of metallothioneins could have a neuroprotective function against the oxidative stress and neuroinflammation involved in AD, indicating that the acute activation by Aβ1-42 oligomers could induce a protective response. We characterized the Aβ plaque burden and morphology in cortical brain slices of AD patients and non-demented control with amyloid plaques. Even though the last group has overall less Aβ plaques, relatively more dense-core plaques were observed. We found no differences in the total number of microglia or morphology between the groups. Further characterization of plaque-associated microglia suggested a reduced phagocytic activity by microglia surrounding dense-core plaques in NDC+-cases. No difference in synaptic density between AD- and NDC+-cases near dense-core or diffuse plaques was detected

The BACH1/Nrf2 Axis in Brain in Down Syndrome and Transition to Alzheimer Disease-Like Neuropathology and Dementia

Down syndrome (DS) is the most common genetic cause of intellectual disability that is associated with an increased risk to develop early-onset Alzheimer-like dementia (AD). The brain neuropathological features include alteration of redox homeostasis, mitochondrial deficits, inflammation, accumulation of both amyloid beta-peptide oligomers and senile plaques, as well as aggregated hyperphosphorylated tau protein-containing neurofibrillary tangles, among others. It is worth mentioning that some of the triplicated genes encoded are likely to cause increased oxidative stress (OS) conditions that are also associated with reduced cellular responses. Published studies from our laboratories propose that increased oxidative damage occurs early in life in DS population and contributes to age-dependent neurodegeneration. This is the result of damaged, oxidized proteins that belong to degradative systems, antioxidant defense system, neuronal trafficking. and energy metabolism. This review focuses on a key element that regulates redox homeostasis, the transcription factor Nrf2, which is negatively regulated by BACH1, encoded on chromosome 21. The role of the Nrf2/BACH1 axis in DS is under investigation, and the effects of triplicated BACH1 on the transcriptional regulation of Nrf2 are still unknown. In this review, we discuss the physiological relevance of BACH1/Nrf2 signaling in the brain and how the dysfunction of this system affects the redox homeostasis in DS neurons and how this axis may contribute to the transition of DS into DS with AD neuropathology and dementia. Further, some of the evidence collected in AD regarding the potential contribution of BACH1 to neurodegeneration in DS are also discussed