Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson's Disease Dementia (PDD).

Parkinson's disease with dementia (PDD) is a neurological disorder that clinically and neuropathologically overlaps with Parkinson's disease (PD) and Alzheimer's disease (AD). Although it is assumed that alpha-synuclein ( α -Syn), amyloid beta (A ß ), and the protein Tau might synergistically induce cholinergic neuronal degeneration, presently the pathological mechanism of PDD remains unclear. Therefore, it is essential to delve into the cellular and molecular aspects of this neurological entity to identify potential targets for prevention and treatment strategies. Cholinergic-like neurons (ChLNs) were exposed to rotenone (ROT, 10 µ M) for 24 h. ROT provokes loss of Δ Ψ m , generation of reactive oxygen species (ROS), phosphorylation of leucine-rich repeated kinase 2 (LRRK2 at Ser935) concomitantly with phosphorylation of α -synuclein ( α -Syn, Ser129), induces accumulation of intracellular A ß (iA ß ), oxidized DJ-1 (Cys106), as well as phosphorylation of TAU (Ser202/Thr205), increases the phosphorylation of c-JUN (Ser63/Ser73), and increases expression of proapoptotic proteins TP53, PUMA, and cleaved caspase 3 (CC3) in ChLNs. These neuropathological features resemble those reproduced in presenilin 1 (PSEN1) E280A ChLNs. Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin- α (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to naïve ChLNs. In conclusion, ROT induces p- α -Syn, iA ß , p-Tau, and cell death in ChLNs, recapitulating the neuropathology findings in PDD. Our report provides an excellent in vitro model to test for potential therapeutic strategies against PDD. Our data suggest that ROT induces a neuropathologic phenotype in ChLNs similar to that caused by the mutation PSEN1 E280A.

Dementia and depression: Biological connections with amyloid ß protein.

Dementia is an umbrella term for a broad group of age-associated neurodegenerative diseases. It is estimated that dementia affects 50 million people worldwide and that Alzheimer's disease (AD) is responsible for up to 75% of cases. Small extracellular senile plaques composed of filamentous aggregates of amyloid ß (Aß) protein tend to bind to neuronal receptors, affecting cholinergic, serotonergic, dopaminergic and noradrenergic neurotransmission, leading to neuroinflammation, among other pathophysiologic processes and subsequent neuronal death, followed by dementia. The amyloid cascade hypothesis points to a pathological process in the cleavage of the amyloid precursor protein (APP), resulting in pathological Aß. There is a close relationship between the pathologies that lead to dementia and depression. It is estimated that depression is prevalent in up to 90% of individuals diagnosed with Parkinson's disease, with varying severity, and in 20 to 30% of cases of Alzheimer's disease. The hypothalamic pituitary adrenal (HPA) axis is the great intermediary between the pathophysiological mechanisms in neurodegenerative diseases and depression. This review discusses the role of Aß protein in the pathophysiological mechanisms of dementia and depression, considering the HPA axis, neuroinflammation, oxidative stress, signalling pathways and neurotransmission.

Probiotics for dementia: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: Dementia is the fifth leading cause of death in the world. Animal studies indicate that in addition to the aging process, intestinal microbiota may play an important role in the neurodegeneration process through the modulation of the gut-brain axis. OBJECTIVE: A systematic review and meta-analysis was conducted to determine the effectiveness of probiotic and synbiotic supplementation on the cognitive function of individuals with dementia. DATA SOURCES: MEDLINE, BVS, SciELO, CENTRAL, Embase, and grey literature were searched from their inception to January 2019. STUDY SELECTION: We included data from randomized clinical trials (RCTs) that addressed dementias and assessed the following outcomes: cognitive function; inflammatory, oxidative stress, and metabolic markers; nutritional status; and intestinal microbiota composition. DATA EXTRACTION: Data searches, article selection, data extraction, and risk-of-bias assessments were performed according to the Cochrane guidelines. Data were pooled by inverse-variance random-effects meta-analyses. GRADE (Grading of Recommendations Assessment, Development, and Evaluations) was used to assess the quality of evidence. RESULTS: Data from 3 RCTs involving 161 individuals with Alzheimer's disease receiving Lactobacillus and Bifidobacterium strains showed no beneficial effect of probiotic supplementation on cognitive function (standardized mean difference, 0.56; 95%CI: -0.06 to 1.18), with very low certainty of evidence. However, probiotic supplementation improved plasma triglycerides, very-low-density lipoprotein cholesterol, insulin resistance, and plasma malondialdehyde. No RCTs included synbiotic supplementation or assessed microbiota composition. CONCLUSION: Current evidence regarding the use of probiotics and synbiotics for individuals with dementia is insufficient to support their clinical application. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no: CRD42018116148.

Calcineurin-Mediated Hippocampal Inflammatory Alterations in Streptozotocin-Induced Model of Dementia.

Although the pathogenesis of Alzheimer's disease (AD) remains unclear, some molecular aspects that precede or accompany the deposit of ß-amyloid in senile plaques attract attention, such as calcium dysregulation and neuroinflammation. It has been suggested that the Ca2+/calmodulin-dependent protein phosphatase, calcineurin (CaN), plays an important role in AD pathogenesis. We hypothesized that CaN activation is involved in the inflammatory changes observed in the streptozotocin (STZ)-induced model of AD. We investigated hippocampal inflammatory and CaN changes in Wistar rats in two moments after intracerebroventricular STZ administration: in the first week (early) and fourth week (later on). We found an early (at 1 week) and persistent (at fourth week) increment in the subunit A of CaN, as well as an increase in the major 48 kDa fragment of this subunit. Glial and inflammatory activation were confirmed by changes of IBA-1, TLR-4, glial fibrillary acidic protein (GFAP), and S100B in the hippocampus. Augmented CaN activity was accompanied by reduced phosphorylation of the pro-apoptotic protein BAD, at Ser 136. Importantly, we found an increase in the nuclear translocation of NFAT4 (more associated to astroglial reactivity) in the hippocampus at 1 and 4 weeks in this model. NFAT3 (more associated with neuronal activation) exhibited an early increase, but decreased later on. Taken together, these data contribute to the understanding of neurochemical changes in the STZ model of sporadic AD, and may explain the persistent inflammatory response in AD, which might occur via the proteolytic activation of CaN, and signaling of NFAT mediated by isoform 4, in activated astrocytes.

Protection of cholinergic and antioxidant system contributes to the effect of Vitamin D3 ameliorating memory dysfunction in sporadic dementia of Alzheimer's type.

OBJECTIVE: Investigate Vitamin D3 (VD3) effect on the Acetylcholinesterase (AChE), oxidative damage and behavioral tests in animals subjected to Intracerebroventicular injection of Streptozotocin (ICV-STZ) simulating a Sporadic Dementia of Alzheimer's Type (SDAT) and treated with VD3 (21 days). METHODS: Animals were divided into eight groups: Vehicle, VD12.5 µg/kg, VD42 µg/kg, VD125 µg/kg, STZ, STZ+VD12.5 µg/kg, STZ+VD42 µg/kg, STZ+VD125 µg/kg. RESULTS: VD3 prevented the increase in AChE in groups of VD42 µg/kg and VD125 µg/kg; in AChE of synaptossomes and TBARS levels prevented the increase in group VD125 µg/kg; in ROS levels there was not a significant difference; for the Carbonyl Content all doses prevented the increase. Total Thiols prevent the decrease in VD42 µg/kg and VD125 µg/kg, and Reduced Glutathione prevented the decrease in VD125 µg/kg, Oxidized Glutathione prevented the increase in VD125 µg/kg. In relation to behavioral tests, the VD3 prevented the increase in time to find (days 2 and 3), in the time to find the platform (day 3) and in time spent in the quadrant (day 2). However, in relation to crossings there was not difference in groups. These results indicated the therapeutic effect of the VD3 in model of STZ in rats.

Effects of Exercise on Inflammatory, Oxidative, and Neurotrophic Biomarkers on Cognitively Impaired Individuals Diagnosed With Dementia or Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

Although the effects of physical exercise (PE) on cognitive function in dementia and mild cognitive impairment (MCI) have been largely studied, its biochemical effect is still poorly explored. The aim of this systematic review was to investigate the effects of PE on inflammatory, oxidative, and neurotrophic biomarkers of participants with MCI or dementia. Six electronic databases, (PubMed, Cochrane Central, Embase, PEDro, PsycINFO, and SportDiscus) were searched for randomized controlled trials assessing the effects of PE on serum and/or plasma biomarkers of elderly participants with MCI or dementia. After selection process, eight studies were included. Meta-analysis was performed by comparison of changes from baseline, using the random effects method. Meta-analysis showed a significant effect of aerobic exercise on interleukin-6 and tumor necrosis factor alpha decrease and positive effects on brain-derived neurotrophic factor expression. As only one study was included with oxidative biomarker assessment, the effects of PE on oxidative process remain unclear. Finally, even though it was possible to observe positive effects of PE on some biomarkers of MCI and dementia individuals, current evidence does not allow drawing specific practical recommendations such as type, frequency, intensity, or duration of PE in these population. Further researches aiming to estimate the PE effectiveness on biomarkers of MCI and Alzheimer's disease are needed.

Metabolic Syndrome and cognitive decline in the elderly: A systematic review.

BACKGROUND: Metabolic Syndrome (MetS) refers to a cluster of metabolic disturbances which is associated with increased risk for vascular and degenerative conditions in general population. Although the relationship between vascular risk factors and dementia is undisputable, additional hazard for cognitive decline in older population with concurrent metabolic disorders still waits to be demonstrated. The present review aims to analyze data on MetS and risk for cognitive decline in elderly persons. METHODS: Database searches were performed in Medline, ISI and PsycINFO for articles assessing cognitive performances of older subjects with MetS. RESULTS: Of a total of 505 studies, 25 were selected for the review. Risk of selection biases was identified in all the studies. Although all articles followed recognized diagnostic recommendations for MetS, minor criteria modifications were detected in most of them. Hyperglycemia was consistently associated with impaired cognitive performances in older individuals, but the role of MetS for cognitive decline and for the onset of dementia showed heterogeneous results. DISCUSSION: Current available data in the literature concerning the impact of MetS on the cognition of older population is inconclusive and based on inconsistent evidence. Differential effects of individual MetS components and factors associated with the age of the sample may have accounted for divergent findings among articles, but larger and higher quality studies in this field are still needed.

Genetic prion disease: Experience of a rapidly progressive dementia center in the United States and a review of the literature.

Although prion diseases are generally thought to present as rapidly progressive dementias with survival of only a few months, the phenotypic spectrum for genetic prion diseases (gPrDs) is much broader. The majority have a rapid decline with short survival, but many patients with gPrDs present as slowly progressive ataxic or parkinsonian disorders with progression over a few to several years. A few very rare mutations even present as neuropsychiatric disorders, sometimes with systemic symptoms such as gastrointestinal disorders and neuropathy, progressing over years to decades. gPrDs are caused by mutations in the prion protein gene (PRNP), and have been historically classified based on their clinicopathological features as genetic Jakob-Creutzfeldt disease (gJCD), Gerstmann-Sträussler-Scheinker (GSS), or Fatal Familial Insomnia (FFI). Mutations in PRNP can be missense, nonsense, and octapeptide repeat insertions or a deletion, and present with diverse clinical features, sensitivities of ancillary testing, and neuropathological findings. We present the UCSF gPrD cohort, including 129 symptomatic patients referred to and/or seen at UCSF between 2001 and 2016, and compare the clinical features of the gPrDs from 22 mutations identified in our cohort with data from the literature, as well as perform a literature review on most other mutations not represented in our cohort. E200K is the most common mutation worldwide, is associated with gJCD, and was the most common in the UCSF cohort. Among the GSS-associated mutations, P102L is the most commonly reported and was also the most common at UCSF. We also had several octapeptide repeat insertions (OPRI), a rare nonsense mutation (Q160X), and three novel mutations (K194E, E200G, and A224V) in our UCSF cohort. © 2016 Wiley Periodicals, Inc.

Effectiveness of individual and group interventions for people with type 2 diabetes / Efetividade das intervenções individual e em grupo junto a pessoas com diabetes tipo 2 / Efectividad de las intervenciones individual y en grupo en personas con diabetes tipo 2

OBJECTIVE: to compare the effectiveness of two educational interventions used by a healthcare provider in the monitoring of individuals with type 2 diabetes mellitus (T2DM), regarding knowledge of the disease, impact on quality of life and adoption of self-care actions. METHODS: comparative, longitudinal, prospective study performed with 150 subjects with type 2 diabetes, analyzed according to the type of participation in the program (individual and/or group). Participants of the individual intervention (II) received nursing consultations every six months and those of the group intervention (GI) took part in weekly meetings for three months. Data were collected through four questionnaires: Identification questionnaire, Problem Areas in Diabetes Questionnaire (PAID), Summary of Diabetes Self-Care Activities Questionnaire (SDSCA) and the Diabetes Knowledge Scale (DKN-A). Data were analyzed using the Friedman and Mann Whitney tests, considering a statistical significance of p ≤ 0.05. RESULTS: there was an increase in knowledge about the disease in the II (p<0.003) and GI (p<0.007), with reduction of the impact on the quality of life in the II (p<0.007) and improvement in self-care actions in the GI (p<0.001). CONCLUSION: in both intervention models improvements were observed in the indicators, over the six month monitoring period. .

OBJETIVO: comparar a efetividade de duas intervenções educativas, utilizadas por uma operadora de saúde, no acompanhamento ao indivíduo com diabetes mellitus Tipo 2 (DM2), quanto ao conhecimento sobre a doença, impacto na qualidade de vida e adoção de ações de autocuidado. MÉTODOS: estudo comparativo, longitudinal, prospectivo, realizado com 150 indivíduos com diabetes tipo 2, analisados conforme a modalidade de participação no programa (individual e/ou em grupo). Os participantes da intervenção individual (II) realizaram consultas de enfermagem a cada seis meses e os da intervenção em grupo (IG), reuniões semanais por três meses. Os dados foram coletados mediante quatro questionários: Questionário de identificação, Questionário de Impacto na Qualidade de Vida em Diabetes (PAID), Questionário de Autocuidado em Diabetes (QAD) e Questionário de Conhecimento do Diabetes (DKN-A). Os dados foram analisados utilizando-se o Teste de Friedman e o Teste de Mann Whitney, considerando significância estatística para p ≤ 0,05. RESULTADOS: verificou-se aumento do conhecimento sobre a doença na II (p<0,003) e na IG (p<0,007), redução do impacto na qualidade de vida na II (p<0,007) e melhora das ações de autocuidado na IG (p<0,001). CONCLUSÃO: em ambos os modelos de intervenção foram observadas melhoras dos indicadores, ao longo dos seis meses de acompanhamento. .

OBJETIVO: comparar la efectividad de dos intervenciones educativas, utilizadas por una operadora de planes de salud, en el acompañamiento al individuo con diabetes mellitus Tipo 2 (DM2), sobre al conocimiento de la enfermedad, impacto en la calidad de vida y adopción de acciones de autocuidado. MÉTODOS: estudio comparativo, longitudinal, prospectivo, realizado con 150 individuos con diabetes tipo 2, analizados conforme la modalidad de participación en el programa (individual y/o en grupo). Los participantes de la intervención individual (II) realizaron consultas de enfermería a cada seis meses y los de intervención en grupo (IG), reuniones semanales por tres meses. Los datos fueron recolectados mediante cuatro cuestionarios: Cuestionario de identificación, Cuestionario de Impacto en la Calidad de Vida en Diabetes (PAID), Cuestionario de Autocuidado en Diabetes (CAD) y Cuestionario de Conocimiento de la Diabetes (DKN-A). Los datos fueron analizados utilizando el test de Friedman y el test de Mann Whitney, considerando significación estadística para p ≤ 0,05. RESULTADOS: se verificó aumento del conocimiento sobre la enfermedad en la II (p<0,003) y en la IG (p<0,007), reducción del impacto en la calidad de vida en la II (p<0,007) y mejoría de las acciones de autocuidado en la IG (p<0,001). CONCLUSIÓN: en los dos modelos de intervención fueron observadas mejorías de los indicadores, a lo largo de los seis meses de acompañamiento. .

Brain health and cognitive and mood disorders in ageing women.

Improved medical, economic and socio-cultural conditions have increased life expectancy, especially for women. The incidence of hypertension, diabetes mellitus, psychiatric and degenerative brain diseases, especially stroke and dementia, are more frequently seen in older people. Each of these conditions can separately, or in combination, result in similar signs and symptoms of cognition, memory, mood and motor function disorders. Therefore, it is important to understand the effects of normal ovarian ageing and the menopause on the nervous system, as well as the hallmarks of disease entities; many of these are described here. Also, the complexity of these issues is increased by the similarity of their effects to those of the polypharmacy and metabolic imbalances that are common in this population. These are complex issues, and it may be difficult and time-consuming to discern between normal brain functional changes and specific pathology in practice. Early evaluation of correctable possibilities, including imaging studies, may be key to management. Referral to specialists for diagnosis before starting clinical treatment is useful to address these issues.

Huperzine A, but not tacrine, stimulates S100B secretion in astrocyte cultures.

AIMS: The loss of cholinergic function in the central nervous system contributes significantly to the cognitive decline associated with advanced age and dementias. Huperzine A (HupA) is a selective inhibitor of acetylcholinesterase (AChE) and has been shown to significantly reduce cognitive impairment in animal models of dementia. Based on the importance of astrocytes in physiological and pathological brain activities, we investigated the effect of HupA and tacrine on S100B secretion in primary astrocyte cultures. S100B is an astrocyte-derived protein that has been proposed to be a marker of brain injury. MAIN METHODS: Primary astrocyte cultures were exposed to HupA, tacrine, cholinergic agonists, and S100B secretion was measured by enzyme-linked immunosorbent assay (ELISA) at 1 and 24h. KEY FINDINGS: HupA, but not tacrine, at 100µM significantly increased S100B secretion in astrocyte cultures. Nicotine (at 100 and 1000µM) was able to stimulate S100B secretion in astrocyte cultures. SIGNIFICANCE: Our data reinforce the idea that AChE inhibitors, particularly HupA, do not act exclusively on the acetylcholine balance. This effect of HupA could contribute to improve the cognitive deficit observed in patients, which are attributed to cholinergic dysfunction. In addition, for the first time, to our knowledge, these data indicate that S100B secretion can be modulated by nicotinic receptors, in addition to glutamate, dopamine and serotonin receptors.

Caffeine consumption prevents memory impairment, neuronal damage, and adenosine A2A receptors upregulation in the hippocampus of a rat model of sporadic dementia.

Intracerebroventricular (icv) streptozotocin (STZ) administration induces pathological and behavioral alterations similar to those observed in Alzheimer's disease (AD) and is thus considered an experimental model of sporadic AD. Since caffeine (an adenosine receptor antagonist) and selective antagonists of adenosine A2A receptors modify the course of memory impairment in different amyloid-ß-based experimental models of AD, we now tested the impact of caffeine on STZ-induced dementia and associated neurodegeneration in the hippocampus as well as on the expression and density of adenosine receptors. Adult male rats received a bilateral infusion of saline or STZ (3 mg/kg, icv), which triggered memory deficits after four weeks, as gauged by impaired object recognition memory. This was accompanied by a reduced NeuN immunoreactivity in the hippocampal CA1 region and an increased expression and density of adenosine A2A receptors (A2AR), but not A1R, in the hippocampus. Caffeine consumption (1 g/L in the drinking water starting 2 weeks before the STZ challenge) prevented the STZ-induced memory impairment and neurodegeneration as well as the upregulation of A2AR. These findings provide the first demonstration that caffeine prevents sporadic dementia and implicate the control of central A2AR as its likely mechanism of action.

Green tea (-)epigallocatechin-3-gallate reverses oxidative stress and reduces acetylcholinesterase activity in a streptozotocin-induced model of dementia.

Alzheimer's disease (AD) is the most prevalent form of dementia. Intracerebroventricular (ICV) infusion of streptozotocin (STZ) provides a relevant animal model of chronic brain dysfunction that is characterized by long-term and progressive deficits in learning, memory, and cognitive behavior, along with a permanent and ongoing cerebral energy deficit. Numerous studies on green tea epigallocatechin gallate (EGCG) demonstrate its beneficial effects on cognition and memory. As such, this study evaluated, for the first time, the effects of sub-chronic EGCG treatment in rats that were submitted to ICV infusion of STZ (3mg/kg). Male Wistar rats were divided into sham, STZ, sham+EGCG and STZ+EGCG groups. EGCG was administered at a dose of 10mg/kg/day for 4 weeks per gavage. Learning and memory was evaluated using Morris' Water Maze. Oxidative stress markers and involvement of the nitric oxide (NO) system, acetylcholinesterase activity (AChE) and glucose uptake were evaluated as well as glial parameters including S100B content and secretion and GFAP content. Our results show that EGCG was not able to modify glucose uptake and glutathione content, although cognitive deficit, S100B content and secretion, AChE activity, glutathione peroxidase activity, NO metabolites, and reactive oxygen species content were completely reversed by EGCG administration, confirming the neuroprotective potential of this compound. These findings contribute to the understanding of diseases accompanied by cognitive deficits and the STZ-model of dementia.

Neuroglial alterations in rats submitted to the okadaic acid-induced model of dementia.

Several types of animal models have been developed to investigate Alzheimer's disease (AD). Okadaic acid (OA), a potent inhibitor of phosphatases 1 and 2A, induces characteristics that resemble AD-like pathology. Memory impairment induced by intra-hippocampal injection of OA has been reported, accompanied by remarkable neuropathological changes including hippocampal neurodegeneration, a paired helical filament-like phosphorylation of tau protein, and formation of ß-amyloid containing plaque-like structures. Rats were submitted to bilateral intrahippocampal okadaic acid-injection (100 ng) and, 12 days after the surgery, behavioral and biochemical tests were performed. Using this model, we evaluated spatial cognitive deficit and neuroglial alterations, particularly astroglial protein markers such as glial fibrillary acidic protein (GFAP) and S100B, metabolism of glutamate, oxidative parameters and alterations in MAPKs. Our results indicate significant hippocampal changes, including increased GFAP, protein oxidation, and phosphorylation of p38(MAPK); and decreases in glutathione content, transporter EAAT2/GLT-1, and glutamine synthetase activity as well as a decrease in cerebrospinal fluid S100B. No alterations were observed in glutamate uptake activity and S100B content. In conclusion, the OA-induced model of dementia caused spatial cognitive deficit and oxidative stress in this model and, for the first time to our knowledge, specific astroglial alterations. Findings contribute to understanding diseases accompanied by cognitive deficits and the neural damage induced by AO administration.

Neuroprotector effect of p,p'-methoxyl-diphenyl diselenide in a model of sporadic dementia of Alzheimer's type in mice: contribution of antioxidant mechanism.

The present study investigated whether the antioxidant activity of p,p'-methoxyl-diphenyl diselenide [(MeOPhSe)(2)] is involved in its protective effect against cognitive impairment induced by streptozotocin (STZ) in a model of sporadic dementia of Alzheimer's type (SDAT). Swiss mice were treated with STZ or vehicle [2 µl of 2·5 mg ml(-1) solution; intracerebroventricularly (i.c.v.)] twice, 48 h apart. (MeOPhSe)(2) (25 mg kg(-1)) or vehicle was orally administered 30 min prior to each STZ treatment. Neuroprotector effect of (MeOPhSe)(2) on the behavioral performance of mice on spatial recognition memory consolidation was investigated in the Y-maze test. After that, mouse brains were removed for measuring antioxidant parameters. (MeOPhSe)(2) protected against the impairment in learning and memory caused by i.c.v. administration of STZ in mice. (MeOPhSe)(2) protected against the increase in reactive species and the reduction of glutathione levels, as well as, the increase in superoxide dismutase and glutathione S-transferase activities caused by STZ in whole brain. These results suggest that antioxidant property is involved, at least in part, in the neuroprotective effect of (MeOPhSe)(2) on SDAT induced by STZ in mice.

Cellular prion protein modulates age-related behavioral and neurochemical alterations in mice.

The cellular prion protein (PrP(C)) is a neuronal-anchored glycoprotein that has been associated with various functions in the CNS such as synaptic plasticity, cognitive processes and neuroprotection. Here we investigated age-related behavioral and neurochemical alterations in wild-type (Prnp(+/+)), PrP(C) knockout (Prnp(0/0)) and the PrP(C) overexpressing Tg-20 mice. Three- or 11 month-old animals were submitted to a battery of behavioral tasks including open field, activity cages, elevated plus-maze, social recognition and inhibitory avoidance tasks. The 11 month-old Prnp(+/+) and Prnp(0/0) mice exhibited significant impairments in their locomotor activity and social recognition memory and increased anxiety-related responses. Remarkably, Tg-20 mice did not present these age-related impairments. The i.c.v. infusion of STI1 peptide 230-245, which includes the PrP(C) binding site, improved the age-related social recognition deficits in Prnp(+/+). In comparison with the two other age-matched genotypes, the 11 month-old Tg-20 mice also exhibited reduced activity of seric acetylcholinesterase, increased expression of the protein synaptophysin and decreased caspase-3 positive-cells in the hippocampus. The present findings obtained with genetic and pharmacological approaches provide convincing evidence that PrP(C) exerts a critical role in the age-related behavioral deficits in mice probably through adaptive mechanisms including apoptotic pathways and synaptic plasticity.

Glial alterations in the hippocampus of rats submitted to ibotenic-induced lesion of the nucleus basalis magnocellularis.

Lesion of the nucleus basalis magnocellularis (nbm) is a suitable approach to study cognitive deficit and behavior alterations involving cholinergic dysfunction, which is associated with the major types of dementia. Cortical astrogliosis also has been described in this model, but it is not clear whether hippocampal astrocytes are activated. In this study, we investigated possible specific astrocyte alterations in the hippocampi of Wistar rats submitted to nbm damage with ibotenic acid, investigating the content and immunohistochemistry of glial fibrillary acidic protein (GFAP), as well as S100B protein content, glutamate uptake and glutamine synthetase activity on the 7th and 28th post-lesion days. Cognitive deficit was confirmed by the step-down inhibitory avoidance task. Interestingly, we found a decrease in GFAP content, S100B content and glutamate uptake activity in the hippocampus on the 28th day after nbm lesion. No alterations were observed in glutamine synthetase activity or in the cerebrospinal fluid S100B content. Although our data suggest caution in the use of nbm lesion with ibotenic acid as a dementia model, it is possible that these alterations could contribute to the cognitive deficit observed in these rats.

In vivo amyloid imaging with PET in frontotemporal dementia.

BACKGROUND: N-methyl[11C]2-(4'methylaminophenyl)-6-hydroxy-benzothiazole (PIB) is a positron emission tomography (PET) tracer with amyloid binding properties which allows in vivo measurement of cerebral amyloid load in Alzheimer's disease (AD). Frontotemporal dementia (FTD) is a syndrome that can be clinically difficult to distinguish from AD, but in FTD amyloid deposition is not a characteristic pathological finding. PURPOSE: The aim of this study is to investigate PIB retention in FTD. METHODS: Ten patients with the diagnosis of FTD participated. The diagnosis was based on clinical and neuropsychological examination, computed tomography or magnetic resonance imaging scan, and PET with 18 Fluoro-2-deoxy-d-glucose (FDG). The PIB retention, measured in regions of interest, was normalised to a reference region (cerebellum). The results were compared with PIB retention data previously obtained from 17 AD patients with positive PIB retention and eight healthy controls (HC) with negative PIB retention. Statistical analysis was performed with a students t-test with significance level set to 0.00625 after Bonferroni correction. RESULTS: Eight FTD patients showed significantly lower PIB retention compared to AD in frontal (p < 0.0001), parietal (p < 0.0001), temporal (p = 0.0001), and occipital (p = 0.0003) cortices as well as in putamina (p < 0.0001). The PIB uptake in these FTD patients did not differ significantly from the HC in any region. However, two of the 10 FTD patients showed PIB retention similar to AD patients. CONCLUSION: The majority of FTD patients displayed no PIB retention. Thus, PIB could potentially aid in differentiating between FTD and AD.

Insulin-degrading enzyme degrades amyloid peptides associated with British and Danish familial dementia.

Familial British dementia (FBD) and familial Danish dementia (FDD) are autosomal dominant disorders characterized by cerebrovascular and parenchymal amyloid deposition and neurofibrillary degeneration. In both conditions, the genetic defects cause the loss of the normal stop codon in the precursor BRI, generating novel 34-residue peptides named ABri and ADan in FBD and FDD, respectively. ABri and ADan show a strong tendency to aggregate into non-fibrillar and fibrillar structures at neutral pH and this property seems to be directly related to neurotoxicity. Here we report that a recombinant insulin-degrading enzyme (rIDE) was capable of degrading monomeric ABri and ADan in vitro more efficiently than oligomeric species. These peptides showed high beta-structure content and were more resistant to proteolysis as compared to the BRI wild-type product of 23 amino acids. Specific sites of cleavage within the C-terminal pathogenic extensions raise the possibility that proteolysis of monomeric soluble precursors by IDE may delay ABri and ADan aggregation in vivo.

Polimorfismo da apolipoproteina E na doenca de Alzheimer tipo tardio: resultados preliminares / Apolipoproteins E polymorphism in Alzheimer's disease: delayed type: preliminary results

A apolipoproteina E (apo E), com funcao no metabolismo de lipideos e transporte de colesterol, tem sido associada tambem a patogenese da doenca de Alzheimer (DA). Este estudo teve como objetivo identificar os genotipos para apo E e a frequencia de seus alelos em individuos com DA tipo tardio (grupo 1) ou sem sintomas de demencia neurodegenerativa (grupo 2). Foram estudados 32 individuos assim distribuidos: grupo 1 = 18 pacientes com idades de 66 a 82 anos (media = 71 anos); grupo 2 = 14 individuos de 65 a 78 anos (media = 69 anos). O DNA foi extraido de leucocitos com amplificacao do segmento de interesse do gene para apo E por PCR (polymerase chain reaction) e submetido a clivagem com enzima Hha I. As frequencias dos alelos nos grupos 1 e 2 foram: 3 - 0,75 e 0,79 (p=0,699), 4 - 0,25 e 0,07 (p=0,035), respectivamente...