Alzheimer's disease (AD) is a degenerative dementia characterized by typical, destructive alterations of neurons (neurofibrillary tangles and amyloid plaques), and glial proliferation. Cytokine-driven inflammatory environment can contribute to the pathogenesis and/or progression of the disease. The aim of the study was to evaluate and compare genotypic and allelic polymorphisms of 13 cytokine genes in 19 Caucasoid AD patients with medium-high level of dementia (assessed by an MMSE < 24) and 20 normal controls affected by non inflammatory neuropsychiatric disease. Polymorphisms in the genes of IL-lA, IL-lB, IL-2, IL-4, IL-6, IL-10, IL-12, IFN-G, TGF-beta, TNF-alpha, and of the cytokine receptors IL-lR, IL-IRA, IL-4RA were investigated. APO-E and ACE gene polymorphisms were carried out in the patient's group only to evaluate a possible association with known genetic risk factors for AD. A highly significant presence of some alleles belonging to anti-inflammatory cytokine genes was found; particularly the C allele for the -590 promoter and T allele for the -1098 promoter of IL-4 appeared in a significantly higher percentage as compared with controls (P < 0.0006 and P < 0.0005, respectively), while a lesser significance was observed for the allele C of the -819 promoter of IL-10 (P < 0.03). Finally, in the group of demented patients for the APO-E gene we found a statistically significant presence of the E4 allele, whereas no difference was found for the polymorphisms of the ACE gene. Our observations corroborate the possible presence of a pro-inflammatory environment in AD patients, partly sustained by the low expression of anti-inflammatory cytokine genes when defined alleles are present. Large cohort studies are necessary in order to assess the real association of some cytokine alleles or haplotypes with AD.

Ample studies have reported on the association between periodontal diseases, a persistent inflammatory process, and other chronic ailments such as cardiovascular diseases, diabetes mellitus, Alzheimer disease, and cancer. Other conditions such as low birth weight and premature delivery due to chorioamnionitis are also known to be linked to poor periodontal health. Although much epidemiologic data support these associations, a cause-and-effect relationship has not been established. The receptor for advanced glycation end products (RAGE) is a multiligand receptor expressed on various cell membranes, including immune, endothelial, and epithelial, and cells of the central nervous system. This receptor, which is frequently associated with proinflammatory responses, has been shown to be activated by various ligands such as high mobility group box-1 (HMGB1/amphoterin), amyloid fibrils, transthyrein, Mac-1 (Integrin Mac-1), as well as advanced glycation end products (AGEs). Recent studies indicate that signaling through RAGE has been implicated as an underlying condition in diverse pathologies including periodontal disease, cardiovascular diseases, diabetes mellitus, Alzheimer disease, cancer, and neurologic conditions. Review of the literature supports the hypothesis that activation of RAGE by ligands in a variety of cell types and tissues may play a role in oral systemic associations. In addition, the ligand cell source and timing of RAGE stimulation may determine the disease produced by this axis. Understanding the distribution and functions of RAGE and its ligands would enhance clinicians' knowledge on pathogenesis of the oral-systemic connection. (Quintessence Int 2010;41:229-237).

BACKGROUND AND PURPOSE:: Individuals with Alzheimer disease (AD) have a higher risk of falls than their cognitively intact peers. This pilot study was designed to assess the feasibility and effectiveness of a small-group balance exercise program for individuals with AD in a day center environment. METHODS:: Seven participants met the inclusion criteria: diagnosis of AD or probable AD, medical stability, and ability to walk (with or without assistive device). We used an exploratory pre- and post-test study design. Participants engaged in a functional balance exercise program in two 45-minute sessions each week for eight weeks. Balance activities were functional and concrete, and the intervention was organized into constant, blocked, massed practice. Outcome measures included Berg Balance Scale (BBS), Timed Up and Go (TUG), and gait speed (GS; self-selected and fast assessed by an instrumented walkway). Data were analyzed by comparing individual change scores with previously identified minimal detectable change scores at the 90% confidence level (MDC90). RESULTS:: Pre- and post-test data were acquired for five participants (two participants withdrew). The BBS improved in all five participants, and improved >/=6.4 points (the MDC90 for the BBS in three participants. Four participants improved their performance on the TUG, and three participants improved >/=4.09 seconds (the MDC90 for the TUG). Self-selected GS increased >/=9.44 cm/sec (the MDC90 for gait speed) in three participants. Two participants demonstrated post-test self-selected GS comparable with their pretest fast GS. DISCUSSION AND CONCLUSIONS:: This pilot study suggests that a small-group functional balance intervention for individuals with AD is feasible and effective. Although participants had no explicit memory of the program, four of five improved in at least two outcome measures. Larger scale functional balance intervention studies with individuals with AD are warranted.

AbstractOBJECTIVES:To evaluate the olfactory function in patients with amnesic mild cognitive impairment (aMCI) and the relationship to the progression from aMCI to Alzheimer disease (AD).DESIGN:Cohort prospective study on aMCI patients at the first evaluation (T0) and at the 18-month follow-up (T1).SETTING:Alzheimer Unit of the University of L'Aquila, Italy.METHODS:Twenty-nine aMCI patients were enrolled in this study.MAIN OUTCOME MEASURES:Olfactory function was studied with the Sniffin' Sticks Screening Test (SSST) and the Sniffin' Sticks Extended Test (SSET). Olfactory functions were related to neurocognitive functions assessed by the Mini-Mental State Examination (MMSE) and the Mental Deterioration Battery (MDB).RESULTS:At T0, aMCI patients showed an olfactory impairment and all of the aMCI patients had lower olfaction scores at T1. At T1, 9 of the 29 aMCI patients (31%) developed AD and had lower mean SSST and SSET scores than 20 aMCI patients who did not develop AD. The most significant relationship was found between olfactory discrimination and visuospatial ability, language skill, and the Rey Immediate test of the MDB and between olfactory identification and the Rey Delayed test.CONCLUSION:Odour discrimination and identification performance correlated more prominently than detection thresholds with performance on neuropsychological tests. We concluded that the olfactory deficit occurs early in aMCI, so we suggest introducing the clinical routine use of the olfactory test for early identification of the progression of the decline from aMCI to AD.

A debilitated 63-year-old man with Alzheimer disease who had a 6 week-history of high-grade fever of unknown etiology became afebrile 1 week after gastrostomy was performed to prevent aspiration. There was no active infiltration on imaging studies, such as chest X-ray films and computed tomography of the chest. Thus, this clinical condition could be described as aspiration-related fever. In other words, imaging studies may not be the gold standard for diagnosing fever related to aspiration.

BACKGROUND: Recently, two large genome wide association studies in Alzheimer disease (AD) have identified variants in three different genes (CLU, PICALM and CR1) as being associated with the risk of developing AD. The strongest association was reported for an intronic single nucleotide polymorphism (SNP) in CLU. METHODOLOGY/PRINCIPAL FINDINGS: To further characterize this association we have sequenced the coding region of this gene in a total of 495 AD cases and 330 healthy controls. A total of twenty-four variants were found in both cases and controls. For the changes found in more than one individual, the genotypic frequencies were compared between cases and controls. Coding variants were found in both groups (including a nonsense mutation in a healthy subject), indicating that the pathogenicity of variants found in this gene must be carefully evaluated. We found no common coding variant associated with disease. In order to determine if common variants at the CLU locus effect expression of nearby (cis) mRNA transcripts, an expression quantitative loci (eQTL) analysis was performed. No significant eQTL associations were observed for the SNPs previously associated with AD. CONCLUSIONS/SIGNIFICANCE: We conclude that common coding variability at this locus does not explain the association, and that there is no large effect of common genetic variability on expression in brain tissue. We surmise that the most likely mechanism underpinning the association is either small effects of genetic variability on resting gene expression, or effects on damage induced expression of the protein.

The research community is showing increasing interest in the analysis of the care trajectory of people with chronic health problems, especially dementias such as Alzheimer's disease. However, despite this interest, there is little research on the initial phases of the care trajectory. The fact that the first symptoms of dementia are generally noticed by those surrounding the elderly person suggests that the recognition of the disease is intimately linked to interactions not only amongst family members but also amongst friends, neighbours and health professionals. This study focuses on the period beginning with the first manifestations of cognitive difficulties and ending with the diagnosis of Alzheimer-type dementia. Interviews with 60 caregivers in Montreal, Canada were used to reconstruct how older people with Alzheimer-type dementia enter into the care trajectory. Our methods consisted of the analysis of social networks, social dynamics and action sequences. Our findings are presented in the form of a typology comprised of 5 pathways of entries into the care trajectory that are structured around the following four principles of the Life Course Perspective: family history, linked lives, human agency and organisational effects. We believe that analyses of the initial phases of the care trajectory, such as this one, are essential for the application of effective early detection and intervention policies. They are also central to informing future studies that seek to understand the care experience in its entirety.

ABSTRACT: BACKGROUND: The extracellular deposition of aggregated amyloid beta-protein is a neuropathological manifestation of Alzheimer disease and Down syndrome. The Amyloid beta-protein is derived from a group of larger differentially spliced proteins, the amyloid protein precursors (APP). Data suggests that the level of APP gene expression could contribute to the pathological processes leading to amyloid depositions. FINDINGS: The 5' untranslated region (UTR) of the APP gene, encompassing 147 base pairs between the transcriptional (+1) and the translational start site, was examined for its role in APP expression. Deletions close to the transcriptional start site reduced expression from the APP promoter in part by transcriptional mechanisms. However, deletions between position +50 and +104 had no effect on transcriptional activity while significantly reducing overall expression from the promoter. A nuclear factor-binding domain designated as DAPB was identified between position +72 and +115 of the 5'-APP-UTR. The binding-recognition sequence was localized between position +96 and +105. The same mutations that eliminated factor-binding also reduced expression from the APP promoter while having no effect on in vitro transcription or the RNA levels transcribed from transfected constructs. CONCLUSIONS: A nuclear factor-binding domain designated as DAPB was identified in the 5'-UTR of the APP gene. Elimination of factor-binding correlated with an overall decline in expression from the APP promoter while in vitro transcription and the total amount of in vivo transcribed RNA remained unaffected. This suggests that the binding-factor may have a function in post-transcriptional regulation, including nuclear export of mRNA.

ABSTRACT: BACKGROUND: Diabetes is considered an independent risk factor for cognitive impairment and some studies observed through neuropsychological tests that cognitive disfunction affects both elderly and younger patients with diabetes. The aims of this study were to evaluate the cognitive status of outpatients with type 2 diabetes and to evaluate factors associated with impaired function. METHODS: A cross-sectional study was conducted in a group of type 2 diabetic outpatients. They were asked to undergo the Mini-Mental State Examination (MMSE) during routine ambulatory visits between April 2006 and January 2007, with the highest pontuation of the test being 30 points. Patients were classified as having possible dementia according to years of study. Exclusion criteria were blindness, illiterately, stroke, Alzheimer disease and psychiatric disorder. Results are presented as median (interquartile range) or mean +/- SD. RESULTS: The study group was composed of 346 type 2 diabetic outpatients (216 females), aged 58,6 +/- 12,1 years and with duration of diabetes of 12,3 +/- 9,1 years. Hypertension was present in 77,2%. The total MMSE score achieved was 26 points (16 - 30) and was correlated with years of study (R2 = 0,39, p < 0,001) and 'per capita' income (R2 = 0,22, p < 0,0001) and duration of diabetes (R2 = - 0,13, p = 0,01). Patients who needed help to take their medications obtained worst performance in the MMSE (23,16 +/- 3,55 vs 25,7 +/- 2,84, p < 0,01) and were more likely to present possible dementia (p < 0,01). Forty two subjects (12.1%) had diagnosis of possible dementia and this was also associated with years of study (p = 0,045). No association was observed between possible dementia and total MMSE scores with A1C levels. CONCLUSIONS: We conclude that patients with type 2 diabetes should be regularly evaluated for their cognitive function, because duration of disease could be associated with decline in cognition. The early implementation of mini mental which is a simple method of execution can be done to detect early stages of dementia. This test could be an important tool to access the ability of patient to understand their disease and treatment.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline associated with a deficit in cholinergic function. Inhibitors of acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE), such as donepezil, galantamine or rivastigmine, are widely prescribed as symptomatic treatments for AD. These agents exhibit a wide variation in their pharmacological properties. Here we review clinical data from 1998 to 2009 investigating the effect of different cholinesterase inhibitor treatments on the levels and activities of cholinesterases in the cerebrospinal fluid (CSF) of AD patients. These studies suggest that treatment with rapidly-reversible cholinesterase inhibitors (e.g. donepezil, galantamine, tacrine) are associated with marked and significant upregulation of AChE activities and protein levels in the CSF of AD patients. In contrast, pseudo-irreversible cholinesterase inhibition (e.g. rivastigmine) is associated with a significant decrease in both CSF AChE and BuChE activities, with no upregulation of CSF protein levels. Additionally, donepezil is associated with a decrease in the level of the AChE-R isoform relative to the synaptic AChE-S isoform, whereas rivastigmine seems to increase this ratio. These findings suggest that these agents exert different effects on CSF cholinesterases. The clinical effects of these pharmacological differences are yet to be fully established.

Background:New in vivo amyloid PET imaging tracers, such as (11)C-PIB, provide possibilities to deeper understand the underlying pathological processes in Alzheimer's disease (AD). In this study we investigated how (11)C-PIB retention is related to cerebral glucose metabolism, episodic memory and CSF biomarkers. Method: Thirty-seven patients with mild AD and 21 patients with mild cognitive impairment (MCI) underwent PET examinations with the amyloid tracer (11)C-PIB, (18)F-FDG for measurement of regional cerebral metabolic rate of glucose (rCMRglc), assessment of episodic memory and assay of cerebral spinal fluid (CSF) levels of amyloid-beta (Abeta(1-42)), total tau and phosphorylated tau respectively. Analyses were performed using Statistical Parametric Mapping (SPM) and regions of interest (ROIs). Results: Pooled data from AD and MCI patients showed strong correlations between (11)C-PIB retention, levels of CSF biomarkers (especially Abeta(1-42)), rCMRglc and episodic memory. Analysis of the MCI group alone revealed significant correlations between (11)C-PIB retention and CSF biomarkers and between CSF biomarkers and episodic memory respectively. A strong correlation was observed in the AD group between rCMRglc and episodic memory as well as a significant correlation between (11)C-PIB retention and rCMRglc in some cortical regions. Regional differences were observed as sign for changes in temporal patterns across brain regions. Conclusions: A complex pattern was observed between pathological and functional markers with respect to disease stage (MCI versus AD) and brain regions. Regional differences over time were evident during disease progression. (11)C-PIB PET and CSF Abeta(42) allowed detection of prodromal stages of AD. Amyloid imaging is useful for early diagnosis and evaluation of new therapeutic interventions in AD.

Alzheimer disease (AD) is accompanied by an activation of the innate immune system, and many epidemiological studies have shown reduced risk for dementia or AD associated with chronic consumption of non-steroidal anti-inflammatory drugs (NSAIDS). These observations led to animal model studies to test the hypothesis that NSAIDs can be disease-modifying for some aspects of AD pathogenesis. NSAIDS cannot only suppress inflammatory targets, which could contribute to neuroprotection, they also slow amyloid deposition by mechanisms that remain unclear. Several large clinical trials with NSAID therapies with AD patients have failed and cyclooxygenase-2 does not appear to be a useful target for disease modifying therapy. However, there may be apolipoprotein E E4 pharmacogenomic effects and a real but delayed positive signal in a large primary prevention trial with naproxen. This encourages researchers to re-address possible mechanisms for a stage-dependent NSAID efficacy, the subject of this review.

The prevalence of Alzheimer disease (AD) and vascular dementia (VD) increases with advancing age, but less so after age 90 years. A retrospective hospital-based study of the relative prevalence of different disorders was performed in 1,110 consecutive autopsy cases of demented elderly in Vienna, Austria (66% females, MMSE <20; mean age 83.3 +/- 5.4 SD years). It assessed clinical, general autopsy data and neuropathology including immunohistochemistry. Neuropathologic diagnosis followed current consensus criteria. Four age groups (7-10th decade) were evaluated. In the total cohort AD pathology was seen in 82.9% ("pure" AD 42.9%; AD + other pathologies 39.9%), VD in 10.8% (mixed dementia, MIX, i.e. AD + vascular encephalopathy in 5.5%); other disorders in 5.7%, and negative pathology in 0.8%. The relative prevalence of AD increased from age 60 to 89 years and decreased slightly after age 90+, while "pure" VD diagnosed in the presence of vascular encephalopathy of different types with low neuritic AD pathology (Braak stages <3; mean 1.2-1.6) decreased progressively from age 60 to 90+; 85-95% of these patients had histories of diabetes, morphologic signs of hypertension, 65% myocardial infarction/cardiac decompensation, and 75% a history of stroke(s). Morphologic subtypes, subcortical arteriosclerotic (the most frequent), multi-infarct encephalopathy, and strategic infarct dementia showed no age-related differences. The relative prevalence of AD + Lewy pathology remained fairly constant with increasing age. Mixed dementia and AD with minor cerebrovascular lesions increased significantly with age, while other dementias decreased. This retrospective study using strict morphologic criteria confirmed increased prevalence of AD with age, but mild decline at age 90+, and progressive decline of VD, while AD + vascular pathologies including MIX showed considerable age-related increase, confirming that mixed pathologies account for most dementia cases in very old persons. A prospective clinicopathologic study in oldest-old subjects showed a significant increase in both AD and cerebral amyloid angiopathy (CAA), but decrease in VD over age 85, while in a small group of old subjects CAA without considerable AD pathology may be an independent risk factor for cognitive decline.

Increasing evidence suggests that phosphorylation may play an important role in the oligomerization, fibrillogenesis, Lewy body (LB) formation, and neurotoxicity of alpha-synuclein (alpha-syn) in Parkinson disease. Herein we demonstrate that alpha-syn is phosphorylated at S87 in vivo and within LBs. The levels of S87-P are increased in brains of transgenic (TG) models of synucleinopathies and human brains from Alzheimer disease (AD), LB disease (LBD), and multiple system atrophy (MSA) patients. Using antibodies against phosphorylated alpha-syn (S129-P and S87-P), a significant amount of immunoreactivity was detected in the membrane in the LBD, MSA, and AD cases but not in normal controls. In brain homogenates from diseased human brains and TG animals, the majority of S87-P alpha-syn was detected in the membrane fractions. A battery of biophysical methods were used to dissect the effect of S87 phosphorylation on the structure, aggregation, and membrane-binding properties of monomeric alpha-syn. These studies demonstrated that phosphorylation at S87 expands the structure of alpha-syn, increases its conformational flexibility, and blocks its fibrillization in vitro. Furthermore, phosphorylation at S87, but not S129, results in significant reduction of alpha-syn binding to membranes. Together, our findings provide novel mechanistic insight into the role of phosphorylation at S87 and S129 in the pathogenesis of synucleinopathies and potential roles of phosphorylation in alpha-syn normal biology.

OBJECTIVE: Paroxysmal kinesigenic dyskinesia (PKD) is characterized by recurrent attacks of dyskinesia, in which movement of one body part produces involuntary movements of other body parts. Surround inhibition (SI), a mechanism for suppression of unwanted movements, could be deficient in these patients. To test this idea, we performed a transcranial magnetic stimulation (TMS) study in drug-naive patients with PKD. METHODS: TMS was set to be triggered by self-initiated flexion of the index finger at different intervals. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest. Normalized MEP amplitudes of the patients' self-triggered TMS sessions at different intervals were compared to those of the controls. RESULTS: During index finger flexion, MEP amplitudes from the little finger muscle were unchanged in both the patients and normal subjects, however, post-movement MEP enhancement observed in the normal subjects was absent in patients with PKD. These results suggest that the functional operation of SI is itself preserved, but that post-movement excitation of surrounding muscles is deficient in PKD. CONCLUSIONS: This finding may represent that the operation of SI is extended to the post-movement period, perhaps as a compensatory mechanism for preventing unwanted movement in surrounding muscles. SIGNIFICANCE: While many types of impaired inhibition have been described previously in PKD, this is the first possible example of increased inhibition.

Abstract Aims: MicroRNAs (miRNAs) are small noncoding RNAs that regulate translational repression of target mRNAs. Accumulating evidence indicates that various miRNAs, expressed in a spatially and temporally controlled manner in the brain, play a key role in neuronal development. However, at present, the pathological implication of aberrant miRNA expression in neurodegenerative events remains largely unknown. To identify miRNAs closely associated with neurodegeneration, we performed miRNA expression profiling of brain tissues of various neurodegenerative diseases. Methods: We initially studied the frontal cortex derived from three amyotrophic lateral sclerosis (ALS) patients by using a microarray of 723 human miRNAs. This was followed by enlargement of study population with quantitative RT-PCR (qRT-PCR) analysis (n = 21). Results: By microarray analysis, we identified upregulation of miR-29a, miR-29b, and miR-338-3p in ALS brains, but due to a great interindividual variation, we could not validate these results by qRT-PCR. However, we found significant down-regulation of miR-29a in Alzheimer disease (AD) brains. The database search on TargetScan, PicTar, and miRBase Target identified neuron navigator 3 (NAV3), a regulator of axon guidance, as a principal target of miR-29a, and actually NAV3 mRNA levels were elevated in AD brains. MiR-29a-mediated downregulation of NAV3 was verified by the luciferase reporter assay. By immunohistochemistry, NAV3 expression was most evidently enhanced in degenerating pyramidal neurons in the cerebral cortex of AD. Conclusions: These observations suggest the hypothesis that underexpression of miR-29a affects neurodegenerative processes by enhancing neuronal NAV3 expression in AD brains.

Abstract Protein aggregation, mitochondrial impairment and oxidative stress are common to multiple neurodegenerative diseases. Homeostasis is regulated by a balanced set of anabolic and catabolic responses, which govern removal and repair of damaged proteins and organelles. Macroautophagy is an evolutionarily conserved pathway for the degradation of long-lived proteins, effete organelles, and protein aggregates. Aberrations in macroautophagy have been observed in Alzheimer, Huntington, Parkinson, motor neuron, and prion diseases. In this review, we will discuss the divergent roles of macroautophagy in neurodegenerative diseases and suggest a potential regulatory mechanism that could determine cell death or survival outcomes. We also highlight emerging data on neurite morphology and synaptic remodeling that indicate the possibility of detrimental functional trade-offs in the face of neuronal cell survival, particularly if the need for elevated macroautophagy is sustained.

Abstract Background The present work is aimed at analysing executive function (EF) in adolescents with Down Syndrome (DS). So far, EF has been analysed mainly in adults with DS, showing a pattern of impairment. However, less is known about children and adolescents with this syndrome. Studying adolescents with DS might help us better understand whether performances on EF tasks of individuals with DS are determined by age or by Alzheimer disease, as some studies suggest, or whether their performances are directly related to DS cognitive profile. Method A battery of EF tasks assessing set shifting, planning/problem-solving, working memory, inhibition/perseveration and fluency, as well as a tasks assessing sustained attention has been administered to a group of 15 adolescents with DS and 15 typically developing children matched for mental age. All EF tasks were selected from previous studies with individuals with intellectual disabilities or from developmental literature and are thought to be useful for the samples considered. Results The present results revealed that the group of individuals with DS performed at a significantly lower level on tasks assessing set shifting, planning/problem-solving, working memory and inhibition/perseveration, but not on the tasks assessing fluency. In addition, individuals with DS demonstrated a greater number of errors and less strategy use for the sustained attention task. Conclusions The results suggest a broad impairment in EF in adolescents with DS, and are consistent with several similar studies conducted with adults with DS. We assume that EF deficit is a characteristic of DS.

Amyloid-beta (Abeta) peptide is commonly found in human Alzheimer's disease (AD) brain and is the main component of Alzheimer amyloid plaques. The predominant forms of Abeta in the human brain are Abeta(1-40) and Abeta(1-42), but Abeta(25-35) fragment, physiologically present in elderly people, is the more toxic region and has been recently found to play a relevant role in AD, due to its peculiar aggregation properties. In this work, we review the current understanding on the conformations and biological activity of Abeta(25-35) exploring aggregation, cytotoxic and neurodegenerative properties of this fundamental Abeta fragment, in order to provide an effective starting point to better approach a pathology spread and problematic as AD.

Previous studies have shown that amyloid beta protein (Abeta ), the essential molecule for the formation of toxic oligomers and, subsequently, Alzheimer plaques, has been associated in vivo with the immune modulator, macrophage migration inhibitory factor (MIF) (17). To further investigate this association in vivo we used the APP transgenic mouse model. Serial brain sections of transgenic APP mice were stained for Abeta plaques and MIF and we observed MIF immunolabeling in microglial cells in association with Abeta plaques in the transgenic mouse brain sections. In addition, functional studies in murine and human neuronal cell lines revealed that Abeta-induced toxicity could be reversed significantly by a small molecule inhibitor of MIF (ISO-1). Finally, to elucidate the role of MIF in Alzheimer's Disease (AD) we measured MIF levels in the brain cytosol and cerebrospinal fluid (CSF) of AD patients and age-matched controls. Our results demonstrate a marked increase of MIF levels within the CSF of AD patients compared with controls. Combined, our results indicate a strong role for MIF in the pathogenesis of AD and furthermore suggest that inhibition of MIF may provide a valuable avenue of investigation for the prevention of disease onset, progression and/or severity.