Platelet phospholipase A<Subscript>2</Subscript> activity in Alzheimer’s disease and mild cognitive impairment

Summary. Phospholipase A₂ (PLA₂) controls the metabolism of phospholipids in cell membranes. In the brain, PLA₂ influences the processing of the amyloid precursor protein (APP) and thus the production of the amyloid-beta peptides (A), which are the major components of the senile plaques in Alzheimers disease (AD). Reduced PLA₂ activity has been reported in brain and in platelets of AD patients. In the present study we investigated PLA₂ activity in platelets from 21 AD patients as compared to 17 healthy elderly controls and 11 individuals with mild cognitive impairment (MCI). Subjects were cognitively assessed by the Mini-Mental State Examination (MMSE) and the CAMDEX schedule. Platelet PLA₂ activity was determined by radio-enzymatic assay, which mainly detected a calcium-independent form of the enzyme present also in the brain (iPLA₂). PLA₂ activity was significantly lower in AD than in controls (p<0.001). Mean PLA₂ activity in MCI individuals was between the values of AD patients and controls, with a subgroup showing PLA as low as the lowest AD patients, but the differences from MCI were not significant from AD and control groups. Lower PLA₂ activity was significantly correlated with a worse cognitive performance both at the MMSE (p=0.001) and the cognitive sub-scale of the CAMDEX inventory (p=0.002). Our data replicate previous findings of reduced platelet PLA₂ activity in AD. Both reduced PLA₂ activity and the correlation with impaired cognition were also reported in brain tissue of AD patients, suggesting thus that the present determinations in platelets may be related to a reduction in the brain. In the brain the inhibition of PLA₂ inhibits the physiological secretion of the APP, a mechanism that increases A formation. Further longitudinal studies should investigate whether those MCI individuals with the lowest PLA₂ values in platelets would be at a higher risk to develop AD during a longitudinal follow up.     

Platelet phospholipase A<Subscript>2</Subscript> activity in patients with Alzheimer’s disease,vascular dementia and ischemic stroke

Summary Phospholipase A₂ (E.C. 3.1.1.4, PLA₂) plays an essential role in metabolism of membrane phospholipids, it is related to inflammatory reactions, secretion of amyloid precursor protein and activation of NMDA receptor after ischemia. In the present study we investigated PLA₂ activity in platelets from 37 Alzheimer’s disease (AD) patients, 32 vascular dementia (VaD) patients and 32 individuals with ischemic stroke as compared to 27 healthy elderly controls. PLA₂ activity was determined using radiometric assay. Mean platelet PLA₂ activity was increased in individuals with Alzheimer’s disease (p < 0.001). In VaD group the enzyme activity was between the values in AD and controls, these differences being significant from both groups. In the group of patients with ischemic stroke mean PLA₂ activity was higher either 48 h after the stroke or 7 days later (in both cases p < 0.001). The results may be particularly interesting in light of the fact, that inhibitors of PLA₂ activity are known.     

The Gab2 in signal transduction and its potential role in the pathogenesis of Alzheimer’s disease

The growth factor receptor-bound protein 2 (Grb2)-associated binder (Gab) proteins are intracellular scaffolding/docking molecules, and participate in multiple signaling pathways, usually acting as the downstream effector of proteintyrosine kinases (PTKs)-triggered signal transduction pathway. When phosphorylated by PTKs, Gab proteins can recruit several signaling molecules (p85, SHP2, and Crk), and subsequently activate multiple transmitting signals that are critical for cell growth, survival, differentiation and apoptosis. Recently, it has been reported that Gab2 polymorphism is associated with the increase in the risk of Alzheimer’s disease (AD) and is involved in the pathogenesis of AD. This review mainly focuses on the structure and function of Gab2 protein and its role in the pathogenesis of AD.     

The plasminogen activating system in the pathogenesis of Alzheimer’s disease

Dementia is a clinical syndrome that affects approximately 47 million people worldwide and is characterized by progressive and irreversible decline of cognitive,behavioral and sesorimotor functions.Alzheimer’s disease(AD)accounts for approximately 60–80%of all cases of dementia,and neuropathologically is characterized by extracellular deposits of insoluble amyloid-β(Aβ)and intracellular aggregates of hyperphosphorylated tau.Significantly,although for a long time it was believed that the extracellular accumulation of Aβwas the culprit of the symptoms observed in these patients,more recent studies have shown that cognitive decline in people suffering this disease is associated with soluble Aβ-induced synaptic dysfunction instead of the formation of insoluble Aβ-containing extracellular plaques.These observations are translationally relevant because soluble Aβ-induced synaptic dysfunction is an early event in AD that precedes neuronal death,and thus is amenable to therapeutic interventions to prevent cognitive decline before the progression to irreversible brain damage.The plasminogen activating(PA)system is an enzymatic cascade that triggers the degradation of fibrin by catalyzing the conversion of plasminogen into plasmin via two serine proteinases:tissue-type plasminogen activator(tPA)and urokinase-type plasminogen activator(uPA).Experimental evidence reported over the last three decades has shown that tPA and uPA play a role in the pathogenesis of AD.However,these studies have focused on the ability of these plasminogen activators to trigger plasmin-induced cleavage of insoluble Aβ-containing extracellular plaques.In contrast,recent evidence indicates that activity-dependent release of uPA from the presynaptic terminal of cerebral cortical neurons protects the synapse from the deleterious effects of soluble Aβvia a mechanism that does not require plasmin generation or the cleavage of Aβfibrils.Below we discuss the role of the PA system in the pathogenesis of AD and the translational relevance of data published to this date.     

The role of synphilin-1 in the pathogenesis of Parkinson’s disease

1 Introduction Parkinson’s disease (PD) is the second most common neurological disorder to affect approximate 0.2% of overall population and 2% of those over the age of 65. The disease is characterized by a triad of cardinal symptoms, including bradykinesia (slowed movement), resting tremor, and rigidity. Progressive degeneration of the dopaminergic (DAergic) neurons which are mostly located in the sub- stantia nigra pars compacta (SNpc), and the formation of eosinophilic inclusions known a…     

The role of memory in awareness of memory deficits in Alzheimer’s disease,schizophrenia, and brain injury

Patients with neuropsychiatric disorders such as Alzheimer’s disease (AD), schizophrenia (Sz), and brain injury (BI) often show memory deficits and lack of awareness of those deficits. This study aimed to investigate the role of memory in awareness of memory deficits and illness in multiple patient groups. Comparison of awareness profiles between groups can reveal common or distinct patterns of awareness and predictors, which may inform theories about the structure of awareness. Using the same standardized measures, AD (N = 27) Sz (N = 31), and BI (N = 26) patients were compared on memory functioning, awareness of illness, and awareness of memory deficits—measured by discrepancy of pretest estimate and actual test scores. All groups were poor at pretest estimation of memory functioning, particularly the AD and BI groups. In AD, patients with the lowest memory functioning rated their performance highest. The BI group and to a lesser extent the AD group showed improved estimations of performance following the memory test. Those with the poorest memory showed the greatest improvement in ratings accuracy post test. The relationship between memory and awareness of memory was stronger than the association between memory and awareness of illness. There was a double dissociation between awareness of memory and awareness of illness across patient groups. The study shows that awareness of memory is linked to memory functioning, while memory is only modestly related to awareness of illness. Dissociations in the role of memory in different domains of awareness and “online” awareness of performance provide information to refine cognitive models of awareness. However, the results should be interpreted with caution given the heterogeneous nature of the sample.     

The role of DJ-1 in the pathogenesis of Parkinson’s disease

1 Introduction Parkinson’s disease (PD) is a common neurodegen- erative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars com- pacta (SNpc). Although the majority of the cases appear to be sporadic, the disorder also can be associated with spe- cific genetic defects, several of which have been identified, including α-synuclein, parkin, PINK1, dardarin (LRRK2) and DJ-1[1]. Vincenzo Bonifati et al. localized a gene for autosomal recessive…     

Blood-brain barrier integrity in the pathogenesis of Alzheimer’s disease

The blood–brain barrier (BBB) tightly controls the molecular exchange between the brain parenchyma and blood. Accumulated evidence from transgenic animal Alzheimer’s disease (AD) models and human AD patients have demonstrated that BBB dysfunction is a major player in AD pathology. In this review, we discuss the role of the BBB in maintaining brain integrity and how this is mediated by crosstalk between BBB-associated cells within the neurovascular unit (NVU). We then discuss the role of the NVU, in particular its endothelial cell, pericyte, and glial cell constituents, in AD pathogenesis. The effect of substances released by the neuroendocrine system in modulating BBB function and AD pathogenesis is also discussed. We perform a systematic review of currently available AD treatments specifically targeting pericytes and BBB glial cells. In summary, this review provides a comprehensive overview of BBB dysfunction in AD and a new perspective on the development of therapeutics for AD.     

Possible roles ofl-phosphoserine in the pathogenesis of Alzheimer’s disease

l-Phosphoserine is a membrane metabolite that is elevated in Alzheimer’s disease brain. This compound has close structural similarity tol-glutamate. Electrophysiological studies indicate thatl-phosphoserine has an acute inhibitory effect, but a delayed excitatory action. A hypothesis is developed based on pharmacological and electrophysiological studies that suggest that the inhibition may be mediated through presynaptic inhibition ofl-glutamate release or perhaps antagonism of postsynaptic kainic acid receptors. The mechanism of the delayed excitation may lie in the tendency ofl-phosphoserine to mimic the action ofl-2-amino-4-phosphonobutyric acid, a blocker of chloride- and calcium-sensitivel-glutamate transport.l-Phosphoserine has also been found to be a competitive antagonist at theN-methyl-d-aspartate recognition site and an antagonist of metabotropic receptor-mediated hydrolysis of inositol phospholipids. Because of these actions, there are several potentially important implications for the elevation ofl-phosphoserine in Alzheimer’s disease, including production memory impairment through presynaptic inhibition ofl-glutamate release or blockade of postsynapticN-methyl-d-aspartate receptors and/or blockade of certainl-glutamate transport sites resulting in increasedl-glutamate levels in the synaptic cleft.     

Changes in the mRNA Levels of α<Subscript>2A</Subscript> and α<Subscript>2C</Subscript> Adrenergic Receptors in Rat Models of Parkinson’s Disease and <Emphasis Type="SmallCaps">l</Emphasis>-DOPA-Induced Dyskinesia

The changes in the mRNA levels of α_2A and α_2C adrenoceptors were investigated in unilateral 6-OHDA-lesioned rat model of Parkinson’s disease and l-DOPA-induced dyskinesia using in situ hybridization. In the untreated 6-OHDA-lesioned rats, α_2A expression was elevated in the locus coeruleus (160 ± 8% and 142 ± 8% in lesioned and unlesioned sides compared to the comparable side in sham-operated rats). Following long-term (21 days, twice daily) treatment with l-DOPA (25 mg/kg l-DOPA methyl ester plus benserazide 6.25 mg/kg) in 6-OHDA-lesioned rats, levels of α_2A adrenoceptor mRNA in the locus coeruleus were decreased, compared to the 6-OHDA-lesioned rats, returning to the levels of α_2A mRNA in the sham-operated rats. α_2A adrenoceptor expression was not changed in other brain regions in any treatment group. There was no change in α_2C expression in the rostral or caudal striatum in which the highest density of α_2C mRNA is present. In conclusion, the data presented in this study demonstrate an increase in α_2A adrenoceptor mRNA in the locus coeruleus in the 6-OHDA-lesioned rat model of Parkinson’s disease. In addition, the data show that repeated treatment with l-DOPA in 6-OHDA-lesioned rats, which induces dyskinesia, restores α_2A mRNA levels. These changes of α_2A mRNA expression, observed in the locus coeruleus, might be of importance to basal ganglia transmission and motor function.     

The role of post-translational modifications of huntingtin in the pathogenesis of Huntington’s disease

Post-translational modifications are rapid, effective and reversible ways to regulate protein stability, localization, function, and their interactions with other molecules. Post-translational modifications usually occur as chemical modifications at amino acid residues, including SUMOylation, phosphorylation, palmitoylation, acetylation, etc. These complex biochemical modifications tightly regulate and control a variety of cellular processes. Several forms of post-translational modifications of huntingtin (Htt) have been described. These modifications affect Htt metabolism, protein-protein interactions and cellular toxicity. Cleavage and clearance of mutant Htt, and the interactions between mutant Htt and other cellular proteins are important biochemical events leading to Huntington’s disease (HD). Therefore, identifying signaling pathways of Htt modification and evaluating the significance of Htt modifications would lead to a better understanding of the normal function of wild-type Htt and the pathogenic mechanisms of mutant Htt.     

The role of the <Emphasis Type="Italic">N</Emphasis>-methyl-D-aspartate receptor in Alzheimer’s disease: Therapeutic potential

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with an unknown etiology. Pathologic processes implicated in AD include β-amyloid-induced synaptic failure; tau hyperphosphorylation; inflammation; oxidative stress; abnormal neurotransmission involving acetylcholine, glutamate, norepinephrine, serotonin, and dopamine; and abnormalities in second messengers, protein kinases, and apoptosis. Although each of these pathways offers potential therapeutic targets, pharmacologic manipulation of the glutamatergic N-methyl-D-aspartate receptor pathway, alone or in combination with cholinergic therapies, is emerging as the next promising strategy for the treatment of AD and vascular dementia.     

The possible role of tissue-type plasminogen activator (tPA) and tPA blockers in the pathogenesis and treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the leading cause of cognitive decline in aged individuals. The pathological hallmarks of AD include the formation of neurofibrillary tangles, along with senile plaques that are mainly composed of the amyloid-β (Aβ) peptide. Several lines of evidence implicate the tPA/plasmin system in AD. One type of cell death observed in AD is excitotoxic neuronal damage, and the tPA/plasmin system participates in excitotoxic cell death. Recent in vitro experiments report that the addition of aggregated Aβ peptide to primary cortical neurons leads to the up-regulation of tPA mRNA expression. Additionally, plasmin (activated by tPA) attenuates Aβ neurotoxicity by degrading the peptide and rendering it inactive. However, there is no evidence to demonstrate an in vivo contribution of the tPA/plasmin system in AD. We are currently examining the effects of the tPA/plasmin system on the deposition and toxicity of the Aβ peptide with in vivo paradigms of AD. We hope to define the contribution of the tPA/plasmin system in the development of AD pathology.     

The Neuropeptide Orexin-A Inhibits the GABA<Subscript>A</Subscript> Receptor by PKC and Ca<Superscript>2+</Superscript>/CaMKII-Dependent Phosphorylation of Its β<Subscript>1</Subscript> Subunit

Orexin-A and orexin-B (Ox-A, Ox-B) are neuropeptides produced by a small number of neurons that originate in the hypothalamus and project widely in the brain. Only discovered in 1998, the orexins are already known to regulate several behaviours. Most prominently, they help to stabilise the waking state, a role with demonstrated significance in the clinical management of narcolepsy and insomnia. Orexins bind to G-protein-coupled receptors (predominantly postsynaptic) of two subtypes, OX₁R and OX₂R. The primary effect of Ox-OXR binding is a direct depolarising influence mediated by cell membrane cation channels, but a wide variety of secondary effects, both pre- and postsynaptic, are also emerging. Given that inhibitory GABAergic neurons also influence orexin-regulated behaviours, crosstalk between the two systems is expected, but at the cellular level, little is known and possible mechanisms remain unidentified. Here, we have used an expression system approach to examine the feasibility, and nature, of possible postsynaptic crosstalk between Ox-A and the GABA_A receptor (GABA_AR), the brain’s main inhibitory neuroreceptor. When HEK293 cells transfected with OX₁R and the α₁, β₁, and γ_2S subunits of GABA_AR were exposed to Ox-A, GABA-induced currents were inhibited, in a calcium-dependent manner. This inhibition was associated with increased phosphorylation of the β₁ subunit of GABA_AR, and the inhibition could itself be attenuated by (1) kinase inhibitors (of protein kinase C and CaM kinase II) and (2) the mutation, to alanine, of serine 409 of the β₁ subunit, a site previously identified in phosphorylation-dependent regulation in other pathways. These results are the first to directly support the feasibility of postsynaptic crosstalk between Ox-A and GABA_AR, indicating a process in which Ox-A could promote phosphorylation of the β₁ subunit, reducing the GABA-induced, hyperpolarising current. In this model, Ox-A/GABA_AR crosstalk would cause the depolarising influence of Ox-A to be boosted, a type of positive feedback that could, for example, facilitate the ability to abruptly awake.     

Dysregulation of cellular calcium homeostasis in Alzheimer’s disease

Calcium is one of the most important intracellular messengers in the brain, being essential for neuronal development, synaptic transmission and plasticity, and the regulation of various metabolic pathways. The findings reviewed in the present article suggest that calcium also plays a prominent role in the pathogenesis of Alzheimer’s disease (AD). Associations between the pathological hallmarks of AD (neurofibrillary tangles [NFT] and amyloid plaques) and perturbed cellular calcium homeostasis have been established in studies of patients, and in animal and cell culture models of AD. Studies of the effects of mutations in the β-amyloid precursor protein (APP) and presenilins on neuronal plasticity and survival have provided insight into the molecular cascades that result in synaptic dysfunction and neuronal degeneration in AD. Central to the neurodegenerative process is the inability of neurons to properly regulate intracellular calcium levels. Increased levels of amyloid β-peptide (Aβ) induce oxidative stress, which impairs cellular ion homeostasis and energy metabolism and renders neurons vulnerable to apoptosis and excitotoxicity. Subtoxic levels of Aβ may induce synaptic dysfunction by impairing multiple signal transduction pathways. Presenilin mutations perturb calcium homeostasis in the endoplasmic reticulum in a way that sensitizes neurons to apoptosis and excitotoxicity; links between aberrant calcium regulation and altered APP processing are emerging. Environmental risk factors for AD are being identified and may include high calorie diets, folic acid insufficiency, and a low level of intellectual activity (bad habits); in each case, the environmental factor impacts on neuronal calcium homeostasis. Low calorie diets and intellectual activity may guard against AD by stimulating production of neurotrophic factors and chaperone proteins. The emerging picture of the cell and molecular biology of AD is revealing novel preventative and therapeutic strategies for eradicating this growing epidemic of the elderly.     

Selective loss of P2Y<Subscript>2</Subscript> nucleotide receptor immunoreactivity is associated with Alzheimer’s disease neuropathology

The uridine nucleotide-activated P2Y(2), P2Y(4) and P2Y(6) receptors are widely expressed in the brain and are involved in many CNS processes, including those which malfunction in Alzheimer's disease (AD). However, the status of these receptors in the AD neocortex, as well as their putative roles in the pathogenesis of neuritic plaques and neurofibrillary tangles, remain unclear. In this study, we used immunoblotting to measure P2Y(2), P2Y(4) and P2Y(6) receptors in two regions of the postmortem neocortex of neuropathologically assessed AD patients and aged controls. P2Y(2) immunoreactivity was found to be selectively reduced in the AD parietal cortex, while P2Y(4) and P2Y(6) levels were unchanged. In contrast, all three receptors were preserved in the occipital cortex, which is known to be minimally affected by AD neuropathology. Furthermore, reductions in parietal P2Y(2) immunoreactivity correlated both with neuropathologic scores and markers of synapse loss. These results provide a basis for considering P2Y(2) receptor changes as a neurochemical substrate of AD, and point towards uridine nucleotide-activated P2Y receptors as novel targets for disease-modifying AD pharmacotherapeutic strategies.     

Prospective memory in Parkinson’s disease: the role of the motor subtypes

Journal of Neurology - Prospective memory (PM) is defined as memory for future intentions and it is typically divided into time-based and event-based PM. Deficit of PM has been reported in patients...