Phospholipid biomarkers in the diagnosis of patients with Alzheimer's disease

Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of the beta-amyloid peptide and the hyperphosphorylation of the tau protein, among other features. The most widely accepted hypothesis on the etiopathogenesis of this disease proposes that the aggregates of the beta-amyloid peptide are the main triggers of tau hyperphosphorylation and the subsequent degeneration of affected neurons. In support of this view, fibrillar aggregates of synthetic beta-amyloid peptide induce tau hyperphosphorylation and cell death in cultured neurons. We have previously reported that lithium inhibits tau hyperphosphorylation and also significantly protects cultured neurons from cell death triggered by beta-amyloid peptide. As lithium is a relatively specific inhibitor of glycogen synthase kinase-3 (in comparison with other protein kinases), and other studies also point to a relevant role of this enzyme, we favor the view that glycogen synthase kinase-3 is a crucial element in the pathogenesis of Alzheimer's disease. In our opinion, the possibility of using lithium, or other inhibitors of glycogen synthase kinase-3, in experimental trials aimed to ameliorate neurodegeneration in Alzheimer's disease should be considered.

Application of Nanobiosensor engineering in the diagnosis of neurodegenerative disorders

Hallmarks of Alzheimer's disease (AD) include the accumulation of amyloid beta peptide (Abeta), hyperphosphorylation of tau protein, and increased inflammatory activity in the hippocampus and cerebral cortex. The receptor for advanced glycation endproducts (RAGE) has been shown to interact with Abeta and to modulate Abeta transport across the blood-brain barrier. Furthermore, RAGE is upregulated at sites of inflammation and its activation results in distinct intracellular signaling cascades in respect to Abeta conformers. Besides Abeta, RAGE interacts with several members of the calcium binding S100 protein family, amphoterin and advanced glycation endproducts. Mounting evidence suggests that RAGE is a key player in the signaling pathways triggered by Abeta and S100 proteins in AD. In this review, we discuss recent discoveries about the crosstalk between RAGE, Abeta and S100 proteins in the pathophysiology of AD.

Alzheimer's Disease (AD) is physiopathologically marked by an accumulation of beta-amyloid peptide (Aβ), hyperphosphorylation of tau protein, inflammation, and oxidative stress in the brain tissue. While new drugs for AD have been approved, novel treatments are still needed. Eplingiella fruticosa (EF) has demonstrated anti-inflammatory and antioxidant properties, which may be beneficial against AD. This study aimed to evaluate the effects of EF leaf essential oil complexed with β-cyclodextrin in a sporadic AD model induced by streptozotocin (STZ). Male Wistar rats (5-6 months old) received an intracerebroventricular STZ injection (3mg/kg) or vehicle, and were orally treated with vehicle, EF (5mg/kg), or donepezil (5mg/kg) for 14 days. Behavioral tests included olfactory discrimination, open field, novel object recognition, sucrose preference, and spontaneous alternation. Upon completion, rats were euthanatized, and their brains were analyzed for Aβ, tau, and IL-1β via immunohistochemistry, and for oxidative stress markers. STZ-treated rats showed memory deficits and anhedonia, accompanied by increased Aβ, tau, and IL-1β immunoreactivity in the olfactory bulb, cortex, hippocampus, and increased TBARS levels in the hippocampus. On the other hand, EF treatment improved short-term and working memory (p < 0.001), and reduced depressive-like behavior (p = 0.02). Additionally, EF treatment decreased Aβ, tau, and IL-1β immunoreactivity in the olfactory bulb, hippocampus and cortex (p < 0.05), and reduced TBARS levels (p = 0.04) and total oxidant status in the hippocampus (p = 0.03), and increased total antioxidant status in the cortex (p = 0.04). These findings suggest EF has neuroprotective effects against STZ-induced damage, indicating its potential as a novel compound for AD treatment.

Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?

The global prevalence of diabetes mellitus and Alzheimer's disease is increasing alarmingly with the aging of the population. Numerous epidemiological data suggest that there is a strong association between type 2 diabetes and an increased risk of dementia. These diseases are both degenerative and progressive and share common risk factors. The amyloid cascade plays a key role in the pathophysiology of Alzheimer's disease. The accumulation of amyloid beta peptides gradually leads to the hyperphosphorylation of tau proteins, which then form neurofibrillary tangles, resulting in neurodegeneration and cerebral atrophy. In Alzheimer's disease, apart from these processes, the alteration of glucose metabolism and insulin signaling in the brain seems to induce early neuronal loss and the impairment of synaptic plasticity, years before the clinical manifestation of the disease. The large amount of evidence on the existence of insulin resistance in the brain during Alzheimer's disease has led to the description of this disease as "type 3 diabetes". Available animal models have been valuable in the understanding of the relationships between type 2 diabetes and Alzheimer's disease, but to date, the mechanistical links are poorly understood. In this non-exhaustive review, we describe the main molecular mechanisms that may link these two diseases, with an emphasis on impaired insulin and IGF-1 signaling. We also focus on GSK3β and DYRK1A, markers of Alzheimer's disease, which are also closely associated with pancreatic β-cell dysfunction and type 2 diabetes, and thus may represent common therapeutic targets for both diseases.

Alzheimer's disease is one of the most challenging threats to the healthcare system in society. One of the main characteristic of Alzheimer's disease (AD) pathology is formation of amyloid plaques from accumulation of amyloid beta peptide. The therapeutic agents that are currently available for AD including acetylcholinesterase inhibitors (AchEIs) and the N-methyl-D-aspartate (NMDA) antagonist are focused on improving the symptoms and do not revert the progression of the disease. This limitation coupled with the burgeoning increase in the prevalence of AD and resultant impact on healthcare economics calls for more substantial treatments for AD. According to the leading amyloid hypothesis, cleavage of amyloid precursor protein to release amyloid beta peptide is the critical event in pathogenesis of Alzheimer's disease. Recently treatment strategies have been focused on modifying the formation, clearance and accumulation of neurotoxic amyloid beta peptide. This article reviews different therapeutic approaches that have been investigated to target amyloid beta ranging from secretase modulators, antiaggregation agents to amyloid immunotherapy. Authors review the different novel drugs which are in clinical trials.

Alzheimer’s disease (AD) represents a growing public health challenge due to its increasing prevalence, projected to reach 150 million cases by 2050. Characterised by neuropathological changes such as the accumulation of beta-amyloid peptide and hyperphosphorylated Tau protein, the disease is related to genetic and environmental factors. The main objective of this research has been to analyse the possible relationship between some cardiovascular factors and AD. This analytical observational case-control study carried out in Castilla y León (Spain), comprised a total of 511 individuals between 60 and 90 years of age, of whom 260 had a diagnosis of AD and the rest were healthy individuals. The results showed that the group with AD were predominantly women, widowed and with primary education, who showed a higher prevalence of family history of the disease. It was also observed that hypertension, cardiac pathology and diabetes mellitus were three cardiovascular risk factors that showed significant increased differences in the group of AD patients compared to the group of control individuals. Although the precise mechanisms require further research, these results underline the importance of addressing complex interactions between genetic and environmental factors in the prevention of AD.

Misfolding and Aggregation of Amyloid Beta Peptide: Single Molecule AFM Force Spectroscopy

Alzheimer’s disease is the most common form of dementia, a debilitating neurodegenerative disease which affects the creation and retention of memories. It affects millions of people across the world, and despite its prevalence an effective treatment or therapy has yet to be discovered. To gain a better understanding of the disease we have investigated a potential candidate gene in the pathway of Alzheimer’s disease, paired homeobox 6 (PAX6), and its role in the mouse model TgCRND8. PAX6 is a developmental gene, necessary for normal development of the eye and several organs in the body. However, it was found to be elevated in Alzheimer’s disease patients, and is a potential candidate gene for an investigation. TgCRND8 mice are a transgenic strain of mice with a double mutation to produce human amyloid protein and convert it in high levels of amyloid-beta, forming plaques similar to those seen in human patients. By utilizing mice brains of different ages and therefore different stages of amyloid plaque development, we were able to visualize the change and increase of PAX6 protein levels in the TgCRND8 mice over time by counting PAX6 containing neuronal cells. In addition to the visualization of PAX6 within a transgenic mouse model, in vitro investigations on the downstream pathways of PAX6 were also performed, specifically regarding the effects on glycogen synthase kinase 3-beta (GSK3β) and its effect on the hyperphosphorylation of tau protein. As the hyperphosphorylation of tau protein has been hypothesized to not only contribute to but also be a cause of Alzheimer’s disease, this study focused on the effects of knocking down PAX6 in vitro on wild-type primary cortical neurons. It was found that there is a dramatic increase in the levels of PAX6 in an in vitro model of Alzheimer’s disease as well as an in vivo model of Alzheimer’s disease, the TgCRND8 mice. By investigating the role that PAX6 plays on the progression of Alzheimer’s disease as well as the localization of the protein in the neuronal cells of a transgenic mouse model, we hope to contribute to a better understanding of the complex causes and pathways of Alzheimer’s disease.

Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer’s disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aβ), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis. The AD susceptibility genes apolipoprotein E (APOE), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1) and clusterin (CLU) are involved in the HSV lifecycle. Polymorphisms in these genes may affect brain susceptibility to HSV-1 infection. APOE, for example, influences susceptibility to certain viral infections, HSV-1 viral load in the brain, and the innate immune response. The AD susceptibility gene cholesterol 25-hydroxylase (CH25H) is upregulated in the AD brain and is involved in the antiviral immune response. HSV-1 interacts with additional genes to affect cognition-related pathways and key enzymes involved in Aβ production, Aβ clearance, and hyperphosphorylation of tau proteins. Aβ itself functions as an antimicrobial peptide (AMP) against various pathogens including HSV-1. Evidence is presented supporting the hypothesis that Aβ is produced as an AMP in response to HSV-1 and other brain infections, leading to Aβ deposition and plaque formation in AD. Epidemiologic studies associating HSV-1 infection with AD and cognitive impairment are discussed. Studies are reviewed supporting subclinical chronic reactivation of latent HSV-1 in the brain as significant in the pathogenesis of AD. Finally, the rationale for and importance of clinical trials treating HSV-1-infected MCI and AD patients with antiviral medication is discussed.

Alzheimer disease (AD) is characterized by neurodegeneration marked by loss of synapses and spines associated with hyperphosphorylation of tau protein. Accumulating amyloid β peptide (Aβ) in brain is linked to neurofibrillary tangles composed of hyperphosphorylated tau in AD. Here, we identify β2-adrenergic receptor (β2AR) that mediates Aβ-induced tau pathology. In the prefrontal cortex (PFC) of 1-year-old transgenic mice with human familial mutant genes of presenilin 1 and amyloid precursor protein (PS1/APP), the phosphorylation of tau at Ser-214 Ser-262 and Thr-181, and the protein kinases including JNK, GSK3α/β, and Ca(2+)/calmodulin-dependent protein kinase II is increased significantly. Deletion of the β2AR gene in PS1/APP mice greatly decreases the phosphorylation of these proteins. Further analysis reveals that in primary PFC neurons, Aβ signals through a β2AR-PKA-JNK pathway, which is responsible for most of the phosphorylation of tau at Ser-214 and Ser-262 and a significant portion of phosphorylation at Thr-181. Aβ also induces a β2AR-dependent arrestin-ERK1/2 activity that does not participate in phosphorylation of tau. However, inhibition of the activity of MEK, an upstream enzyme of ERK1/2, partially blocks Aβ-induced tau phosphorylation at Thr-181. The density of dendritic spines and synapses is decreased in the deep layer of the PFC of 1-year-old PS1/APP mice, and the mice exhibit impairment of learning and memory in a novel object recognition paradigm. Deletion of the β2AR gene ameliorates pathological effects in these senile PS1/APP mice. The study indicates that β2AR may represent a potential therapeutic target for preventing the development of AD.

Alzheimer’s disease (AD) belongs to the class of neurodegenerative disorder and is biochemically characterized by amyloid-β (Aβ) plaques deposition, accumulation of neurofibrillary tangles (NFTs) accumulation and ultimately neuronal loss. Even though, the progress made in developing efficient AD therapy, there is no effective drug capable to stop and/or slow down AD progression. In the current article, we investigated the neuroprotective effect of Khaya grandifololia crude extract and fraction 2 against Aβ 42 -induced cytotoxicity and hyperphosphorylation of tau protein in differentiated neuronal cells (IMR32). Reactive oxygen species production, apoptosis and mitochondrial dynamics and function, synaptic protein, and tau phosphorylation were evaluated using fluorescence microscopy and immunoblotting. Cell viability was assessed using the MTT assay. Findings revealed that exposure of differentiated IMR32 cells to Aβ 42 alone induced the impairment of mitochondrial dynamics, decrease synaptic protein expression and increase hyperphosphorylation of tau protein (phospho tau181). In contrast, the presence of crude extract and KGf2 significantly inhibited the cleavage of Caspase-3 activation. In addition, the levels of synaptic proteins (Symptosomal associated protein 25 and Synaptosin) and superoxide dismutase were restored upon treatment with crude extract and fraction 2. Hyperphosphorylation of tau protein (Thr181) and ERK (Thr202/Tyr205) activities were also significantly reduced after treatment with crude extract and fraction 2. Our findings suggest that KG extract is a potential source for candidate drug against AD and may contribute to the development of efficient therapeutic strategy against AD.

Microtubule-associated protein tau (MAPT) hyperphosphorylation and aggregation, are two hallmarks of a family of neurodegenerative disorders collectively referred to as tauopathies. In many tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and Pick’s disease, tau aggregates are found associated with highly sulfated polysaccharides known as heparan sulfates (HSs). In AD, amyloid beta (Aβ) peptide aggregates associated with HS are also characteristic of disease. Heparin, an HS analog, promotes misfolding, hyperphosphorylation and aggregation of tau protein in vitro. HS also provides cell surface receptors for attachment and uptake of tau seeds, enabling their propagation. These findings point to HS-tau interactions as potential therapeutic targets in tauopathies. The zebrafish genome contains genes paralogous to MAPT, genes orthologous to HS biosynthetic and chain modifier enzymes, and other genes implicated in AD. The nervous system in the zebrafish bears anatomical and chemical similarities to that in humans. These homologies, together with numerous technical advantages, make zebrafish a valuable model for investigating basic mechanisms in tauopathies and identifying therapeutic targets. Here, we comprehensively review current knowledge on the role of HSs in tau pathology and HS-targeting therapeutic approaches. We also discuss novel insights from zebrafish suggesting a role for HS 3-O-sulfated motifs in tau pathology and establishing HS antagonists as potential preventive agents or therapies for tauopathies.