Current Alzheimer Research - Volume 9, Issue 4, 2012

Recent data indicate that Tau immunotherapy may be relevant for interfering with neurofibrillary degeneration in Alzheimer disease and related disorders referred to as Tauopathies. The key question for immunotherapy is the choice of the epitope to target. Abnormal phosphorylation is a well-described post-translational modification of Tau proteins and may be a good target. In the present study, we investigated the effects of active immunization against the pathological epitope phospho-Ser422 in the THY-Tau22 transgenic mouse model. Starting from 3-6 months of age, THY-Tau22 mice develop hippocampal neurofibrillary tangle-like inclusions and exhibit phosphorylation of Tau on several AD-relevant Tau epitopes. Three month-old THY-Tau22 mice were immunized with a peptide including the phosphoserine 422 residue while control mice received the adjuvant alone. A specific antibody response against the phospho-Ser422 epitope was observed. We noticed a decrease in insoluble Tau species (AT100- and pS422 immunoreactive) by both biochemical and immunohistochemical means correlated with a significant cognitive improvement using the Y-maze. This Tau immunotherapy may facilitate Tau clearance from the brain toward the periphery since, following immunization, an increase in Tau concentrations was observed in blood. Overall, the present work is, to our knowledge, the first one to demonstrate that active immunotherapy targeting a real pathological epitope such as phospho-Ser422 epitope is efficient. This immunotherapy allows for Tau clearance and improves cognitive deficits promoted by Tau pathology in a well-defined Tau transgenic model.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by extracellular accumulation of amyloid deposits and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated Tau proteins. Brainderived neurotrophic factor (BDNF) is a neurotrophic factor playing a critical role in hippocampal synaptic plasticity and memory and whose levels have been shown reduced in AD brains. While recent data support a pivotal role of β-amyloid peptides towards BDNF decrease, whether Tau pathology impacts on BDNF expression remains unknown so far. In the present study, we have evaluated this relationship using quantitative PCR, Western blot and ELISA in the THY-Tau22 transgenic strain, known to display a progressive development of both hippocampal AD-like Tau pathology and memory impairments. We observed that Tau pathology was not associated with down-regulation of BDNF at the protein and mRNA levels in this model, suggesting that the alteration of BDNF homeostasis observed in AD patients’ brains might rather be ascribed to amyloid pathology.

Alzheimer’s Disease (AD) is the most common neurodegenerative disorder leading to dementia. A major neuropathological hallmark of AD is the deposition of amyloid-β protein (Aβ) in the form of neuritic plaques. Aβ is formed by the sequential cleavage of amyloid-β precursor protein (APP) by β- and γ -secretase. It was recently suggested that TMP21 is a novel member of the γ-secretase complex which negatively regulates APP cleavage at the γ-site, but does not affect cleavage of APP or Notch at the ε-site . In vitro knockdown of TMP21 increases Aβ production and AD patients have less TMP21 expressed in their brains, suggesting that a deficiency in TMP21 may exacerbate AD pathology. TMP21 is most commonly known for its role in vesicle trafficking. Here we present the most recent research on TMP21 in relation to AD, including TMP21’s roles in the modulation of γ-secretase activity and protein trafficking.

End-stage Alzheimer's disease (AD) involves drastic modifications in neuronal molecular and cellular processes, but little is known about the dynamics of these modifications during disease initiation and progression. Here, we report meta-analysis of 100 publicly available Microarray datasets using threshold-independent analysis. We found that different patients react to AD progression by variable single transcript alterations which however lead to similar changes in functional gene groups. Stratification by patients' cognitive deterioration pre`sented hippocampal-specific mRNA alterations which involved progressively changed gene categories and indicate changes in epigenetic state and microRNA profiles. In addition, datasets from laser-captured neurofibrillary tangles-free hippocampal neurons and transcript classification by cell types identified many of these changes in neurons. Intriguingly, we discovered that early-onset decline in alternative splicing, protein folding and transport transcripts occur concurrently with decreases in synaptic transmission, whereas at later stages these changes progressed into enhanced oxidative stress and inflammation. Our findings open new venues for identifying novel targets for intervention with AD progression.

Background: Engagement in cognitively stimulating activities (CA) and leisure time physical activity (PA) have been associated with maintaining cognitive performance and reducing the likelihood of cognitive decline in older adults. However, neural mechanisms underlying protective effects of these lifestyle behaviors are largely unknown. In the current study, we investigated the effect of self-reported PA and CA on hippocampal volume and semantic processing activation during a fame discrimination task, as measured by functional magnetic resonance imaging (fMRI). We also examined whether possession of the apolipoprotein E (APOE) ?4 allele could moderate the effect of PA or CA on hippocampal structure or function. Methods: Seventy-eight healthy, cognitively intact older adults underwent baseline neuropsychological assessment, hippocampal volume measurement via manually-traced structural MRI, and task-activated fMRI. Results: After 18 months, 27 participants declined by one standard deviation or more on follow-up neuropsychological testing. Logistic regression analyses revealed that CA alone or in combination with baseline hippocampal structure or functional activity did not predict the probability of cognitive decline. In contrast, PA interacted with APOE ε4 status such that engagement in PA reduced the risk of cognitive decline in APOE ε4 carriers only. Furthermore, the benefits of PA appeared to diminish with reduced functional activity or volume in the hippocampus. Conclusions: Our findings suggest that increased leisure time PA is associated with reduced probability of cognitive decline in persons who are at high risk for AD. The beneficial effects of PA in this group may be related to enhancement of the functional and structural integrity of the hippocampus.

Activation of inflammatory processes is observed within the brain as well as periphery of subjects with Alzheimer's disease (AD). Whether or not inflammation represents a possible cause of AD or occurs as a consequence of the disease process, or, alternatively, whether the inflammatory response might be beneficial to slow the disease progression remains to be elucidated. The cytokine IL-18 shares with IL-1 the same pro-inflammatory features. Consequent to these similarities, IL-18 and its endogenous inhibitor, IL-18BP, were investigated in the plasma of AD patients versus healthy controls (HC). An imbalance of IL-18 and IL-18BP was observed in AD, with an elevated IL-18/IL-18BP ratio that might be involved in disease pathogenesis. As part of the inflammatory response, altered levels of RANTES, MCP-1 and ICAM- 1, molecules involved in cell recruitment to inflammatory sites, were observed in AD. Hence, correlations between IL-18 and other inflammatory plasma markers were analyzed. A negative correlation was observed between IL-18 and IL-18BP in both AD and HC groups. A positive correlation was observed between IL-18 and ICAM-1 in AD patients, whereas a negative correlation was evident in the HC group. IL-18 positively correlated with Aβ in both groups, and no significant correlations were observed between IL-18, RANTES and MCP-1. An important piece of evidence supporting a pathophysiologic role for inflammation in AD is the number of inflammatory mediators that have been found to be differentially regulated in AD patients, and specific ones may provide utility as part of a biomarker panel to not only aid early AD diagnosis, but follow its progression.

Toll-like receptor 4 (TLR4) represents a reasonable functional and positional candidate gene for Alzheimer’s disease (AD) as it is located within the previous identified linkage region of AD on chromosome 9q, and functionally is involved in the microglia-mediated inflammatory response, amyloid-β (Aβ) plaque formation and Aβ clearance. To test whether variants in the TLR4 gene are associated with late-onset AD (LOAD), we organized a multicenter study of 785 subjects (399 cases and 386 matched controls) in a Han Chinese population. Ten single nucleotide polymorphisms (SNPs) that span the TLR4 gene, from approximately 5 kb of the predicted 5’-untranslated region (UTR) to approximately 6 kb of the predicted 3’- UTR, were selected and their associations with LOAD risk factors were assessed. With respect to allelic diversity, the minor alleles of seven SNPs (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, rs7037117, and rs7045953) in TLR4 showed consistent protective effects against the risk of developing LOAD. With regard to genotypic diversity, individuals carrying at least one minor allele of each SNP above had a consistently lower risk of LOAD than those with no copies of the minor alleles (ORs ranging from 0.445 to 0.637). rs7045953, located in the 3’-UTR of TLR4, was most strongly associated with LOAD, and when incorporated into a haplotype with rs10759930, the strongest association was detected (P = 1.7x10-6, Pc =1.0x10-4). Our data suggests that the TLR4 gene contributes to the susceptibility for LOAD in Han Chinese.

Background: Alzheimer’s disease (AD) has a complex genetic etiology, and as a result many genes have been studied to determine how they might be involved with the disease. Amyloidogenic effects have been broadly linked with familial forms of the disease, though certain genes such as UBQLN1 could also play a role in prodromal phases such as amnesic mild cognitive impairment (MCI). Aim: The aim of this study is to examine the role of the UBQ-8i (rs12344615) functional polymorphism in the UBQLN1 gene as a risk factor for MCI and AD and its possible synergies with apolipoprotein gene E (APOE). Material & Methods: 215 MCI patients, 347 sporadic AD sufferers and 238 healthy controls from the Basque Country (Spain) were analysed. Clinical criteria and neuro-psychiatric tests were used to establish the diagnostic groups. SNP, UBQ-8i and the APOE gene were genotyped via real-time polymerase chain reaction (rtPCR), polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLPs) respectively. Multinomial logistic regression models were used to determine the risk for MCI and AD. Results: Allele C of rs12344615 of the UBQLN1 gene is not a risk factor for MCI or AD (OR = 0.88, CI95% 0.60-1.31 p7equal;s0.542 and OR = 0.73, CI95% 0.51-1.02 p=0.079, respectively). Moreover, genotypes with at least one C allele are observed not to show synergies with APOE*E4 in MCI or with AD sufferers. Conclusion: Allele C of polymorphism UBQ-8i of the UBQLN1 gene is not an independent risk factor for MCI or AD. Moreover, this allele is not observed to have any synergy effects with APOE*E4.

More than a third of Alzheimer’s disease (AD) patients show nigrostriatal pathway disturbances, resulting in akinesia (inability to initiate movement) and bradykinesia (slowness of movement). The high prevalence of this dysfunction of dopaminergic neuron in the nigrostriatal pathway in AD suggests that the risk factors for AD appear also significant risk factors for substantia nigra pars compacta (SNpc) lesions. Previously, we have demonstrated that allopregnanolone (AP?) promotes neurogenesis and improves the cognitive function in a triple transgenic mouse model of AD (3xTgAD). In this study, we sought to exam 1) the SNpc lesions in 3xTgAD mice and 2) the impact of APα on promoting the regeneration of new dopaminergic neurons in SNpc of the 3xTgAD mice. The number of Nissl-stained total neurons, tyrosine hydroxylase (TH) positive neurons, and BrdU/TH double positive newly formed neurons were analyzed with unbiased stereology. In the SNpc of 3xTgAD mice, TH positive neurons was 47 ± 18 &percnt (p = 0.007), total neurons was 62 ± 11.6 % (p = 0.016), of those in the SNpc of non-Tg mice, respectively. APα treatment increased the TH positive neurons in the SNpc of 3xTgAD mice to 93.2 ± 18.5 % (p = 0.021 vs. 3xTgAD vehicle) and the total neurons to 84.9 ± 6.6 (p = 0.046 vs. 3xTgAD vehicle) of non-Tg mice. These findings indicate that there is a loss of neurons, specifically the TH positive neurons in SNpc of 3xTgAD mice, and that APα reverses the lesion in SNpc of 3xTgAD by increasing the formation of new TH neurons.

We performed a clinical trial to evaluate the effects of the histamine subtype-3 receptor inverse agonist MK- 0249 on cognition in AD patients. Mild-to-moderate AD patients were randomized 1:1 to 4 weeks of double-blind daily treatment with oral MK-0249 5-mg or placebo. Pharmacokinetic and PET data suggested that MK-0249 5-mg daily would achieve approximately 85% brain receptor occupancy at Cmax in elderly patients. Primary efficacy measures were the short Computerized-Neuropsychological-Test-Battery (CNTB) summary score and ADAS-Cog score. A secondary efficacy measure was a Cognition Summary Score summarizing results from 7 cognitive tests. Of 144 patients randomized, 132 completed 4 weeks (MK-0249 = 65, placebo = 67). Most patients (88.2%) were on concomitant symptomatic AD treatment. There were no significant differences between treatments on primary and secondary endpoints at week 4: short CNTB summary score = 0.89 (95% CI: -0.74,2.52); ADAS-Cog score = -0.25 (95% CI: -1.61,1.11); Cognition Summary Score = 1.38 (95% CI: -0.64,3.40). MK-0249 was generally well tolerated but was associated with an increased percentage of patients with adverse events (41/73; 56.2%) versus placebo (18/70; 25.7%). Adverse events in >5% of patients on MK-0249 were diarrhea (8.2% vs. 2.9%), headache (8.2% vs. 1.4%), muscle spasms (5.5% vs. 0%), insomnia (5.5% vs. 0%) and stomach discomfort (5.5% vs. 0%). MK-0249 5-mg once daily over 4 weeks was not effective in improving cognitive function in mild to moderate AD patients who were on concomitant symptomatic AD treatment. (ClinicalTrials.gov trial registration, NCT00420420).

The pathophysiology of Alzheimer's disease (AD) is influenced by sorting-protein related receptor (sorLa) that is less expressed in AD patients. The gene encoding sorLa (SORL1) has been investigated as a susceptibility factor for late-onset AD (LOAD) with conflicting results. Our objectives were to confirm the association between SORL1 SNPs and LOAD in two independent South-European centers and to perform a mega-analysis of published samples. We analyzed three SORL1 SNPs (intron 6: rs668387; rs689021; rs641120) from the Greece-Italy Genetic Association Study on lateonset AD (GIGAS_LOAD). Greek sample included 96 patients with LOAD (DSM-IV) and 120 unrelated controls. In Italy, a community-based sample is ongoing. 47 LOAD patients and 165 controls were recruited until study endpoint. These samples and previously published ones (Alzgene) were pooled as in a single study. A test for trend was used to analyze genotype association. In the GIGAS_LOAD sample no association was detected between SORL1 genotypes and LOAD. Conversely all SNPs were associated with LOAD in mega-analysis based on ordinal classification of genotypes (Armitage's test: p<0.001). Although our analysis of pooled samples has positive results for the association between SORL1 and AD, there is substantial heterogeneity across studies. Thus further examination into SORL1 SNPs and the population is necessary to determine the role of SORL1 in LOAD.

In a previous in vitro study, the standardized turmeric extract, HSS-888, showed strong inhibition of Aβ aggregation and secretion in vitro, indicating that HSS-888 might be therapeutically important. Therefore, in the present study, HSS-888 was evaluated in vivo using transgenic ‘Alzheimer’ mice (Tg2576) over-expressing Aβ protein. Following a six-month prevention period where mice received extract HSS-888 (5mg/mouse/day), tetrahydrocurcumin (THC) or a control through ingestion of customized animal feed pellets (0.1% w/w treatment), HSS-888 significantly reduced brain levels of soluble (∼40%) and insoluble (∼20%) Aβ as well as phosphorylated Tau protein (∼80%). In addition, primary cultures of microglia from these mice showed increased expression of the cytokines IL-4 and IL-2. In contrast, THC treatment only weakly reduced phosphorylated Tau protein and failed to significantly alter plaque burden and cytokine expression. The findings reveal that the optimized turmeric extract HSS-888 represents an important step in botanical based therapies for Alzheimer’s disease by inhibiting or improving plaque burden, Tau phosphorylation, and microglial inflammation leading to neuronal toxicity.

Autobiographical memory (AM) comprises memories of one’s own past that are characterized by a sense of subjective time and autonoetic awareness. AM deficits are among the major complaints of patients with Alzheimer’s disease (AD) even in early or preclinical stages. However, little is known on the association between cerebral alterations and AM in mild cognitive impairment (MCI) and AD. In the current study, patients with AD or MCI and healthy controls underwent high-resolution magnetic resonance imaging (MRI) and neuropsychological testing including semi-structured assessment of semantic and episodic AM of distinct lifetime periods. In MRI analysis, FSL-FIRST was used to automatically ascertain volume and shape of the hippocampal formation. Episodic, but not semantic AM loss was associated with morphological changes of the hippocampus, primarily involving the left hemisphere. According to shape analyses, these associations referred to regionally specific rather than global atrophy of the hippocampus. Our study demonstrates that loss of episodic AM early in the course of AD is associated with regionally confined hippocampal atrophy, thus supporting the multiple trace theory for the role of the hippocampus in episodic AM. Our findings are not only relevant for the understanding of memory function, but may also contribute to facilitating the early diagnosis of AD.

Mild cognitive impairment (MCI) often represents a prodromal form of dementia, conferring a significantly higher risk of converting to probable Alzheimer's disease (AD). The aim of this study is to characterise the differences of grey matter (GM) distribution and dynamics between progressive and stable MCI subjects during a 2 year period preceding the conversion to AD. We included 48 stable MCI and 12 progressive MCI cases based on the availability of 3 serial scans acquired with approximately 1 year scan interval. For the progressive MCI group, the third scan was acquired at the time of the clinical diagnosis of AD, while the first two scans were acquired approximately 2 and 1 years earlier. For the stable MCI group, the three scans were acquired at approximately 1 year intervals during a period free from significant cognitive decline. We used longitudinal voxel-based morphometry (VBM) for mapping the progression of GM loss over time. For the progressive MCI group, the cross-sectional analysis revealed areas of lower GM volumes in the parahippocampal gyrus, precuneus and posterior cingulate 12 months before the AD diagnosis. For the longitudinal VBM analysis the progressive MCI group revealed increased GM loss in cortical regions belonging to the temporal neocortex, parahippocampal cortex, and cingulate gyrus. The frontal lobe, insula and the cerebellum were also affected. This accelerated atrophy may offer new insights into the understanding of neurodegenerative pathology and the clinical relevance of these changes remains to be verified by subsequent studies.