The role of the ubiquitin proteasome system in Alzheimer's disease.

Today, Alzheimer's disease (AD) is one of the most important age-related neurodegenerative diseases, but its etiology remains still unknown. Since the discovery that the hallmark structures of this disease i.e. the formation of amyloid fibers could be the product of ubiquitin-mediated protein degradation defects, it has become clear that the ubiquitin-proteasome system (UPS), usually essential for protein repair, turnover and degradation, is perturbed in this disease. Different aspects of normal and pathological aging are discussed with respect to protein repair and degradation via the UPS, as well as consequences of a deficit in the UPS in AD. Selective protein oxidation may cause protein damage, or protein mutations may induce a dysfunction of the proteasome. Such events eventually lead to activation of cell death pathways and to an aberrant aggregation or incorporation of ubiquitinated proteins into hallmark structures. Aggresome formation is also observed in other neurodegenerative diseases, suggesting that an activation of similar mechanisms must occur in neurodegeneration as a basic phenomenon. It is essential to discuss therapeutic ways to investigate the UPS dysfunction in the human brain and to identify specific targets to hold or stop cell decay.

A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease.

The postsynaptic density protein PSD-95 is a major element of synapses. PSD-95 is involved in aging, Alzheimer's disease (AD) and numerous psychiatric disorders. However, contradictory data about PSD-95 expression in aging and AD have been reported. Indeed in AD versus control brains PSD-95 varies according to regions, increasing in the frontal cortex, at least in a primary stage, and decreasing in the temporal cortex. In contrast, in transgenic mouse models of aging and AD PSD-95 expression is decreased, in behaviorally aged impaired versus unimpaired rodents it can decrease or increase and finally, it is increased in rodents grown in enriched environments. Different factors explain these contradictory results in both animals and humans, among others concomitant psychiatric endophenotypes, such as depression. The possible involvement of PSD-95 in reactive and/or compensatory mechanisms during AD progression is underscored, at least before the occurrence of important synaptic elimination. Thus, in AD but not in AD transgenic mice, enhanced expression might precede the diminution commonly observed in advanced aging. A two-compartments cell model, separating events taking place in cell bodies and synapses, is presented. Overall these data suggest that AD research will progress by untangling pathological from protective events, a prerequisite for effective therapeutic strategies.

Synchronizability of EEG-Based Functional Networks in Early Alzheimer's Disease.

Recently graph theory and complex networks have been widely used as a mean to model functionality of the brain. Among different neuroimaging techniques available for constructing the brain functional networks, electroencephalography (EEG) with its high temporal resolution is a useful instrument of the analysis of functional interdependencies between different brain regions. Alzheimer's disease (AD) is a neurodegenerative disease, which leads to substantial cognitive decline, and eventually, dementia in aged people. To achieve a deeper insight into the behavior of functional cerebral networks in AD, here we study their synchronizability in 17 newly diagnosed AD patients compared to 17 healthy control subjects at no-task, eyes-closed condition. The cross-correlation of artifact-free EEGs was used to construct brain functional networks. The extracted networks were then tested for their synchronization properties by calculating the eigenratio of the Laplacian matrix of the connection graph, i.e., the largest eigenvalue divided by the second smallest one. In AD patients, we found an increase in the eigenratio, i.e., a decrease in the synchronizability of brain networks across delta, alpha, beta, and gamma EEG frequencies within the wide range of network costs. The finding indicates the destruction of functional brain networks in early AD.

Evolution of source EEG synchronization in early Alzheimer's disease.

Alzheimer's disease (AD) disrupts functional connectivity in distributed cortical networks. We analyzed changes in the S-estimator, a measure of multivariate intraregional synchronization, in electroencephalogram (EEG) source space in 15 mild AD patients versus 15 age-matched controls to evaluate its potential as a marker of AD progression. All participants underwent 2 clinical evaluations and 2 EEG recording sessions on diagnosis and after a year. The main effect of AD was hyposynchronization in the medial temporal and frontal regions and relative hypersynchronization in posterior cingulate, precuneus, cuneus, and parietotemporal cortices. However, the S-estimator did not change over time in either group. This result motivated an analysis of rapidly progressing AD versus slow-progressing patients. Rapidly progressing AD patients showed a significant reduction in synchronization with time, manifest in left frontotemporal cortex. Thus, the evolution of source EEG synchronization over time is correlated with the rate of disease progression and should be considered as a cost-effective AD biomarker.

Analysis of glial acidic fibrillary protein in the human entorhinal cortex during aging and in Alzheimer's disease.

Glial fibrillary acidic protein, GFAP, is a major intermediate filament protein of glial cells and major cytoskeletal structure in astrocytes. The entorhinal cortex has a key role in memory function and is one of the first brain areas to reveal hallmark structures of Alzheimer's disease and therefore provides an ideal tissue to investigate incipient neurodegenerative changes. Here we have analyzed age- and disease-related occurrence and composition of GFAP in the human entorhinal cortex by using one- and two-dimensional electrophoresis, Western blots and immunocytochemistry combined with confocal microscopy. A novel monoclonal antibody, GF-02, was characterized that mainly reacted with intact GFAP molecules and indicated that more acidic and soluble GFAP forms were also more susceptible to degradation. GFAP and vimentin increased with aging and in Alzheimer's disease (AD). Two-dimensional electrophoresis and Western blots revealed a complex GFAP pattern, both in aging and AD with different modification and degradation forms. Immunohistochemistry indicated that reactive astrocytes mainly accumulated in relation to neurofibrillary tangles and senile plaques in deeper entorhinal cortex layers. GFAP may be used as an additional but not exclusive diagnostic tool in the evaluation of neurodegenerative diseases because its levels change with age and respond to senile plaque and tangle formation.

Demyelination of superficial white matter in early Alzheimer's disease: a magnetization transfer imaging study.

Assuming selective vulnerability of short association U-fibers in early Alzheimer's disease (AD), we quantified demyelination of the surface white matter (dSWM) with magnetization transfer ratio (MTR) in 15 patients (Clinical Dementia Rating Scale [CDR] 0.5-1; Functional Assessment Staging [FAST]: 3-4) compared with 15 controls. MTRs were computed for 39 areas in each hemisphere. We found a bilateral MTR decrease in the temporal, cingulate, parietal, and prefrontal areas. With linear discriminant analysis, we successfully classified all the participants with 3 variates including the cuneus, parahippocampal, and superior temporal regions of the left hemisphere. The pattern of dSWM changed with the age of AD onset. In early onset patients, we found bilateral posterior demyelination spreading to the temporal areas in the left hemisphere. The late onset patients showed a distributed bilateral pattern with the temporal and cingulate areas strongly affected. A correlation with Mini Mental State Examination (MMSE), Lexis, and memory tests revealed the dSWM impact on cognition. A specific landscape of dSWM in early AD shows the potential of MTR imaging as an in vivo biomarker superior to currently used techniques.

Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease.

With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, galantamine, rivastigmine and memantine. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors with different pharmacodynamic and pharmacokinetic profiles. Donepezil inhibits selectively the acetylcholinesterase and has a long elimination half-life (t½) of 70 h. Galantamine is also a selective acetylcholinesterase inhibitor, but also modulates presynaptic nicotinic receptors. It has a t½ of 6-8 h. Donepezil and galantamine are mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4 in the liver. Rivastigmine is a so-called 'pseudo-irreversible' inhibitor of acetylcholinesterase and butyrylcholinesterase. The t½ of the drug is very short (1-2 h), but the duration of action is longer as the enzymes are blocked for around 8.5 and 3.5 h, respectively. Rivastigmine is metabolised by esterases in liver and intestine. Memantine is a non-competitive low-affinity antagonist of the NMDA receptor with a t½ of 70 h. Its major route of elimination is unchanged via the kidneys. Addressing the issue of inter-patient variability in treatment response might be of special importance for the vulnerable population taking anti-dementia drugs. Pharmacogenetic considerations might help to avoid multiple medication changes due to non-response and/or adverse events. Some pharmacogenetic studies conducted on donepezil and galantamine reported an influence of the CYP2D6 genotype on the pharmacokinetics of the drugs and/or on the response to treatment. Moreover, polymorphisms in genes of the cholinergic markers acetylcholinesterase, butyrylcholinesterase, choline acetyltransferase and paraoxonase were found to be associated with better clinical response to acetylcholinesterase inhibitors. However, confirmation studies in larger populations are necessary to establish evidence of which subgroups of patients will most likely benefit from anti-dementia drugs. The aim of this review is to summarize the pharmacodynamics and pharmacokinetics of the four commonly used anti-dementia drugs and to give an overview on the current knowledge of pharmacogenetics in this field.

Alzheimer disease: curly fibers and tangles in organs other than brain.

The filamentous brain lesions that define Alzheimer disease (AD) consist of senile plaques and neurofibrillary tangles. Undulated pathological filaments--curly fibers or neuropil threads--also occur in the neuropil. Beta-amyloid precursor proteins are synthesized by many cells outside the central nervous system and recently, deposition of beta-amyloid-protein was reported to occur in non-neuronal tissues. In addition, increasing data claim the importance of chronic inflammation in the pathogenesis of AD. These observations suggest that AD may be a widespread systemic disorder. Here we report that pathological argyrophilic filaments with histochemical properties of amyloid showing striking morphological similarity to curly fibers and/or tangles accumulate not only in ependymal layer and in epithelial cells of choroid plexus, but also in several other organs (e.g. liver, pancreas, ovary, testis, thyroid) in AD. The ependyma, choroid plexus, and various organs of 39 autopsy cases were analyzed. In search of curly fiber and tangle-like changes in organs other than brain, 395 blocks from 21 different tissues of 24 AD cases, 5 cases with discrete or moderate AD-type changes, and 10 control cases were investigated. We found in non-neuronal cells "curly fibers" or "tangles" immunoreactive with antibodies to P component, Tau-protein, ubiquitin, fibronectin, and Apolipoprotein-E, but lacking immunoreactivity with antibodies to neurofilament proteins. Ultrastructurally they consist of densely packed straight and paired helical filaments and closely resemble neurofibrillary tangles and neuropil threads. These observations indicate that the formation of "curly fibers" and "tangles" is not unique to the central nervous system. The results suggest that AD might be a systemic disorder or that similar fibrillary changes to tangles and curly fibers may also be associated with other amyloidosis than beta-amyloidosis. Further investigations are necessary to understand the pathogenetic interest of these fibrillary changes outside the CNS.

SET translocation is associated with increase in caspase cleaved amyloid precursor protein in CA1 of Alzheimer and Down syndrome patients.

Caspase cleaved amyloid precursor protein (APPcc) and SET are increased and mislocalized in the neuronal cytoplasm in Alzheimer Disease (AD) brains. Translocated SET to the cytoplasm can induce tau hyperphosphorylation. To elucidate the putative relationships between mislocalized APPcc and SET, we studied their level and distribution in the hippocampus of 5 controls, 3 Down syndrome and 10 Alzheimer patients. In Down syndrome and Alzheimer patients, APPcc and SET levels were increased in CA1 and the frequency of both localizations in the neuronal cytoplasm was high in CA1, and low in CA4. As the increase of APPcc is already present at early stages of AD, we overexpressed APPcc in CA1 and the dentate gyrus neurons of adult mice with a lentiviral construct. APPcc overexpression in CA1 and not in the dentate gyrus induced endogenous SET translocation and tau hyperphosphorylation. These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation.

Cerebral and extracerebral cholesterol metabolism and CSF markers of Alzheimer's disease.

The disturbances of the cholesterol synthesis and metabolism described in Alzheimer's disease (AD) may be both a consequence of the neurodegenerative process and a contributor to the pathogenesis. These putative relationships and their underlying mechanisms are not well understood. The aim of this study was to evaluate the relationship between the cerebral and extracerebral cholesterol synthesis and metabolism, and the AD pathology as reflected by CSF markers in humans. We evaluated the relationships between the plasma and the cerebrospinal fluid (CSF) concentrations of cholesterol, the cholesterol precursors lanosterol, lathosterol and desmosterol, and the cholesterol elimination products 24S-hydroxycholesterol and 27-hydroxycholesterol, and the CSF markers for AD pathology Aβ1-42 and p-tau181 in 86 subjects with normal cognition and in 107 AD patients. CSF desmosterol, cholesterol and 24S-hydroxycholesterol in the AD group, and CSF 24S-hydroxycholesterol in the control group correlated with the p-tau181 levels. Neither CSF nor plasma concentrations of the included compounds correlated with the CSF Aβ1-42 levels. In multivariate regression tests including age, gender, albumin ratio, number of the APOEε4 alleles, and diagnosis, p-tau181 levels independently predicted the CSF desmosterol, cholesterol and 24S-hydroxycholesterol concentrations. The associations remained significant for CSF cholesterol and 24S-hydroxycholesterol when analyses were separately performed in the AD group. The results suggest that alterations of CNS cholesterol de novo genesis and metabolism are related to neurodegeneration and in particular to the cerebral accumulation of phosphorylated tau.

Plasma lipoprotein-associated phospholipase A2 activity in Alzheimer's disease, amnestic mild cognitive impairment, and cognitively healthy elderly subjects: a cross-sectional study.

ABSTRACT: INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulating enzyme with pro-inflammatory and oxidative activities associated with cardiovascular disease and ischemic stroke. While high plasma Lp-PLA2 activity was reported as a risk factor for dementia in the Rotterdam study, no association between Lp-PLA2 mass and dementia or Alzheimer's disease (AD) was detected in the Framingham study. The objectives of the current study were to explore the relationship of plasma Lp-PLA2 activity with cognitive diagnoses (AD, amnestic mild cognitive impairment (aMCI), and cognitively healthy subjects), cardiovascular markers, cerebrospinal fluid (CSF) markers of AD, and apolipoprotein E (APOE) genotype. METHODS: Subjects with mild AD (n = 78) and aMCI (n = 59) were recruited from the Memory Clinic, University Hospital, Basel, Switzerland; cognitively healthy subjects (n = 66) were recruited from the community. Subjects underwent standardised medical, neurological, neuropsychological, imaging, genetic, blood and CSF evaluation. Differences in Lp-PLA2 activity between the cognitive diagnosis groups were tested with ANOVA and in multiple linear regression models with adjustment for covariates. Associations between Lp-PLA2 and markers of cardiovascular disease and AD were explored with Spearman's correlation coefficients. RESULTS: There was no significant difference in plasma Lp-PLA2 activity between AD (197.1 (standard deviation, SD 38.4) nmol/min/ml) and controls (195.4 (SD 41.9)). Gender, statin use and low-density lipoprotein cholesterol (LDL) were independently associated with Lp-PLA2 activity in multiple regression models. Lp-PLA2 activity was correlated with LDL and inversely correlated with high-density lipoprotein (HDL). AD subjects with APOE-ε4 had higher Lp-PLA2 activity (207.9 (SD 41.2)) than AD subjects lacking APOE-ε4 (181.6 (SD 26.0), P = 0.003) although this was attenuated by adjustment for LDL (P = 0.09). No strong correlations were detected for Lp-PLA2 activity and CSF markers of AD. CONCLUSION: Plasma Lp-PLA2 was not associated with a diagnosis of AD or aMCI in this cross-sectional study. The main clinical correlates of Lp-PLA2 activity in AD, aMCI and cognitively healthy subjects were variables associated with lipid metabolism.

Lipoprotéine(a): de l'athérosclérose à Alzheimer [Lipoprotein (a) in Alzheimer's atherosclerosis].

Lipoprotein(a) [Lp(a)] is an enigmatic lipoprotein particle present in the plasma from humans, great apes and hedgehogs. Plasma levels of Lp(a) vary widely between individuals and are largely determined by specific sequences within the gene encoding apo(a), the unique highly polymorphic glycoprotein attached to apoB of low density lipoprotein (LDL) to form Lp(a). Elevated plasma concentrations of LP(a) are associated with the premature development of atherosclerosis. A major goal of our laboratory is to better understand the metabolism of Lp(a) and its function in humans. We have identified unexpected and large variations in plasma Lp(a) levels during renal disease, HIV-infection and in sepsis. Moreover, we have observed an association between Lp(a) and Alzheimer disease. Taken together, our observations suggest that Lp(a) may constitute a novel target in our fight against cardiovascular and neurodegenerative disorders.

Role of the JNK-interacting protein 1/islet brain 1 in cell degeneration in Alzheimer disease and diabetes.

Numerous epidemiological studies and some pharmacological clinical trials show the close connection between Alzheimer disease (AD) and type 2 diabetes (T2D) and thereby, shed more light into the existence of possible similar pathogenic mechanisms between these two diseases. Diabetes increases the risk of developing AD and sensitizers of insulin currently used as diabetes drugs can efficiently slow cognitive decline of the neurological disorder. Deposits of amyloid aggregate and hyperphosphorylation of tau, which are hallmarks of AD, have been also found in degenerating pancreatic islets beta-cells of patients with T2D. These events may have a causal role in the pathogenesis of the two diseases. Increased c-Jun NH(2)-terminal kinase (JNK) activity is found in neurofibrillary tangles (NFT) of AD and promotes programmed cell death of beta-cells exposed to a diabetic environment. The JNK-interacting protein 1 (JIP-1), also called islet brain 1 (IB1) because it is mostly expressed in the brain and islets, is a key regulator of the JNK pathway in neuronal and beta-cells. JNK, hyperphosphorylated tau and IB1/JIP-1 all co-localize with amyloids deposits in NFT and islets of AD and patients with T2D. This review discusses the role of the IB1/JIP-1 and the JNK pathway in the molecular pathogenesis of AD and T2D.

Defective tumor necrosis factor-alpha-dependent control of astrocyte glutamate release in a transgenic mouse model of Alzheimer disease.

The cytokine tumor necrosis factor-alpha (TNFalpha) induces Ca2+-dependent glutamate release from astrocytes via the downstream action of prostaglandin (PG) E2. By this process, astrocytes may participate in intercellular communication and neuromodulation. Acute inflammation in vitro, induced by adding reactive microglia to astrocyte cultures, enhances TNFalpha production and amplifies glutamate release, switching the pathway into a neurodamaging cascade (Bezzi, P., Domercq, M., Brambilla, L., Galli, R., Schols, D., De Clercq, E., Vescovi, A., Bagetta, G., Kollias, G., Meldolesi, J., and Volterra, A. (2001) Nat. Neurosci. 4, 702-710). Because glial inflammation is a component of Alzheimer disease (AD) and TNFalpha is overexpressed in AD brains, we investigated possible alterations of the cytokine-dependent pathway in PDAPP mice, a transgenic model of AD. Glutamate release was measured in acute hippocampal and cerebellar slices from mice at early (4-month-old) and late (12-month-old) disease stages in comparison with age-matched controls. Surprisingly, TNFalpha-evoked glutamate release, normal in 4-month-old PDAPP mice, was dramatically reduced in the hippocampus of 12-month-old animals. This defect correlated with the presence of numerous beta-amyloid deposits and hypertrophic astrocytes. In contrast, release was normal in cerebellum, a region devoid of beta-amyloid deposition and astrocytosis. The Ca2+-dependent process by which TNFalpha evokes glutamate release in acute slices is distinct from synaptic release and displays properties identical to those observed in cultured astrocytes, notably PG dependence. However, prostaglandin E2 induced normal glutamate release responses in 12-month-old PDAPP mice, suggesting that the pathology-associated defect involves the TNFalpha-dependent control of secretion rather than the secretory process itself. Reduced expression of DENN/MADD, a mediator of TNFalpha-PG coupling, might account for the defect. Alteration of this neuromodulatory astrocytic pathway is described here for the first time in relation to Alzheimer disease.

Differential phosphorylation of tau proteins during kitten brain development and Alzheimer's disease.

Differential distribution and phosphorylation of tau proteins were studied in developing kitten brain by using several antibodies, and was compared to phosphorylation in Alzheimer's disease. Several antibodies demonstrated the presence of phosphorylated tau proteins during kitten brain development and identified pathological structures in human brain tissue. Antibody AD2, recognized tau in kittens and adult cats, but reacted in Alzheimer's tissue only with a pathological tau form. Antibody AT8 was prominent in developing kitten neurons and was found in axons and dendrites. After the first postnatal month this phosphorylation type disappeared from axons. Furthermore, dephosphorylation of kitten tau with alkaline phosphatase abolished immunoreactivity of AT8, but not that of AD2, pointing to a protection of the AD2 epitope in cats. Tau proteins during early cat brain development are phosphorylated at several sites that are also phosphorylated in paired helical filaments during Alzheimer's disease. In either event, phosphorylation of tau may play a crucial role to modulate microtubule dynamics, contributing to increased microtubule instability and promoting growth of processes during neuronal development or changing dynamic properties of the cytoskeleton and contributing to the formation of pathological structures in neurodegenerative diseases.