Current Alzheimer Research - Volume 8, Issue 2, 2011

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Alzheimer's disease (AD) is the most common form of neurodegenerative dementias worldwide. Amyloid-β deposition, neurofibrillary tangle formation and Neuroinflammation are the major pathogenetic mechanisms that in concert lead to memory dysfunction and decline of cognition. To date, there is no curative treatment for AD. Epidemiological analysis support the notion that sustained intake of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk and delay the onset of AD. In contrast, therapeutic studies testing NSAID efficacy in AD patients have not yielded positive results. This suggests that either the investigated drugs have not addressed the mechanism of action required for mediating beneficial effects or that NSAIDs are effective at stages way before clinical onset of symptoms. The NSAIDs concerned are pleiotrophic in nature and interact with more than one pathomechanism. Therefore evidence for more than one neuroprotective action of NSAIDs has been put forward and it seems likely that some of the drugs act at multiple levels through more than one molecular mechanism. Some, even may not only be beneficial, but negative actions may be overruled by protective effects. Within these mechanisms, modulation of γ-secretase activity, the activation of the peroxisome proliferator- activated receptor-γ, binding to prostaglandin receptors or interactions at the blood-brain barrier may account for the observed protection from AD. This article reviews the current knowledge and views on the above mechanisms and critically discusses current obstacles and the potential as future AD therapeutics.

The importance of inflammatory processes in Alzheimer's disease (AD) progression has been confirmed during the past decade by the intensive investigation of inflammatory mediators in the brain of AD patients as well as by the genetic and drug manipulation of animal models of AD. Imaging studies have revealed that the activation of microglia occurs in early stages of the disease, even before plaque and tangle formation, and is correlated with early cognitive deficits. In this review, we analyze how different risk factors, such as trauma, stroke, infection, and metabolic diseases can lead to an acceleration of the inflammatory response in the AD brain and to an increased risk of developing this disorder. The use of imaging techniques for early detection of glial activation which offer the advantage of investigating how potential antiinflammatory therapies may influence disease progression and levels of cognition is also discussed.

The idea that an inflammatory process is involved in Alzheimer's disease (AD) was proposed already hundred years ago but only the past twenty years inflammation-related proteins have been identified within plaques. A number of acute-phase proteins colocalize with the extracellular amyloid fibrils, the so called Aβ-associated proteins. Activated microglia and astrocytes surrounding amyloid deposits express receptors of innate immunity and secrete pro-inflammatory cytokines. In this paper we review the evidence for involvement of innate immunity in the early stages of the pathological cascade of AD. Diffuse plaques, the initial neuropathological lesion in the cerebral neocortex, contain next to Aβ also apolipoprotein E, clusterin, α1-antichymotrypsin and activated complement proteins. Interestingly, genetic studies have shown gene-loci to be associated with AD for all these proteins, except α1-antichymotrpsin. Fibrillar Aβ can, through stimulation of toll-like receptors and CD-14 on glial cells, activate pathways for increased production of pro-inflammatory cytokines. This pathway, inducing production of proinflammatory cytokines, is under genetic control. The finding that the responsiveness of the innate immunity is higher in offspring with a parental history of late-onset AD indicates heritable traits for AD that are related to inflammatory processes. Prospective epidemiological studies which report that higher serum levels of certain acute-phase proteins are associated with cognitive decline or dementia provide additional evidence for the early involvement of inflammation in AD pathogenesis. The reviewed neuropathological, epidemiological and genetic findings show evidence for involvement of the innate-immunity in the early stages of pathological cascade as well as for the hypothesis that the innate immunity contributes to the etiology of late-onset AD.

Alzheimer disease (AD) is characterized by a progressive cognitive decline and accumulation of β-amyloid (Aβ) forming senile plaques that are associated with inflammatory molecules and cells. Resident microglia and newly differentiated cells that are derived from the bone marrow are found in the vicinity of Aβ plaques. Although these two types of microglia are not distinguishable by specific markers in the brain, they seem to possess different phenotype and functions. In mouse models of AD, bone marrow-derived microglia (BMDM) have been shown to delay or stop the progression of AD and preventing their recruitment exacerbates the pathology. Transplantation of competent hematopoietic stem cells or their genetic modifications ameliorate cognitive functions, reduce Aβ accumulation and prevent synaptic dysfunctions. Improving the recruitment of genetically-modified BMDM may be considered as a powerful new therapeutic strategy to counteract AD. Here we review the role of microglia subsets in AD and how these cells have a great potential to fight against Aβ accumulation and cognitive impairment.

Alzheimer's disease (AD) is pathologically defined by presence of intracellular neurofibrillary tangles and extracellular amyloid plaques comprised of amyoid-β (Aβ) peptides. Despite local recruitment of brain microglia to sites of amyloid deposition, these mononuclear phagocytes ultimately fail at restricting β-amyloid plaque formation. On the other hand, it is becoming increasingly clear that professional phagocytes from the periphery possess Aβ clearance aptitude. Yet, in order to harness this beneficial innate immune response, effective strategies must be developed to coax monocytes/ macrophages from the periphery into the brain. It has previously been suggested that Aβ ‘immunotherapy’ clears cerebral Aβ deposits via mononuclear phagocytes, and recent evidence suggests that targeting transforming growth factor- β-Smad 2/3 signaling and chemokine pathways such as Ccr2 impacts blood-to-brain trafficking of these cells in transgenic mouse models of AD. It has also been shown that the fractalkine receptor (Cx3cr1) pathway plays a critical role in chemotaxis of mononuclear phagocytes toward neurons destined for death in AD model mice. In order to translate these basic science findings into AD treatments, a key challenge will be to develop a new generation of pharmacotherapeutics that safely and effectively promote recruitment of peripheral amyloid phagocytes into the AD brain.

The occurrence of a plaque-dependent inflammation in Alzheimer's disease has been extensively documented in both human specimens and transgenic models of the disease. Since insoluble plaques are present in AD patients from early preclinical stages of the pathology, the point at which neuroinflammation first occurs in the progression of the AD pathology is still unknown. In this review we discuss the clinical and experimental evidence for the occurrence of inflammation in preclinical, asymptomatic phases of the progression of the AD pathology. In particular, we discuss the evidence from different transgenic models suggesting that a pro-inflammatory process might even be initiated prior to plaque deposition. The factors responsible for the early, pre-plaque inflammation are reviewed, with particular emphasis on the role of soluble Aβ-oligomers. Furthermore, we analyze the consequences of the microglial activation and the deregulation of NGF metabolism, in the context of the earliest amyloid pathology. Finally, we propose MMP-9 as a promising biomarker for signalling early stages of an ongoing CNS inflammation.

Background: This analysis aimed to identify an operational, clinically relevant definition of response achieved in short-term clinical trials to support the identification of patients with Alzheimer's disease (AD) who would benefit most from long-term galantamine therapy. Methods: Data were analyzed from 6 randomized placebo-controlled trials of up to 6 months' duration, which included patients with mild to moderate AD receiving maintenance doses of galantamine 16-24 mg/day, and from 12 open-label extensions (galantamine 24 mg/day maintenance therapy). Assessments included changes from baseline in the 11-item AD Assessment Scale-Cognitive subscale (ADAS-Cog 11). Results: Pooled analysis of the 5- 6 month trial data showed that at the trial endpoint (2-5 months after reaching maintenance doses), the proportions of galantamine- (n=1,173) versus placebo-treated patients (n=801) with probable AD categorized according to “improved”, “stable” or “non-rapid decline” criteria, were 45.8% versus 27.2%, 59.5% versus 37.1%, and 87.6% versus 69.7%, respectively (observed cases analysis), whilst changes in ADAS-Cog 11 scores versus baseline were -4.9, -4.7 and -2.9 points, respectively, for “improved”, “stable” and “non-rapid decline” galantamine-treated patients (-1.5 points for galantamine recipients overall). “Improved” or “stable” galantamine-treated patients displayed mean improvement in ADAS-Cog 11 scores over baseline until 18 months after starting treatment, and attenuated deterioration thereafter; for galantaminetreated patients exhibiting “non-rapid decline”, mean ADAS-Cog 11 score returned to baseline after approximately 12 months. Conclusions: Patients who demonstrate improvement, stability, or limited cognitive decline 2-5 months after reaching maintenance doses of galantamine are more likely to experience continued benefit from long-term galantamine therapy.

The objective of this study was to elucidate an association between Apo- Eε4 allele and CSF biomarkers Aβ42 and tau for the diagnosis of Alzheimer's Disease (AD) patients. Aβ42 and tau protein concentrations in CSF were measured by using ELISA assays. The levels of Aβ42 were found to be decreased where as tau levels increased in AD patients. Moreover in AD patients Apo-Eε4 allele carriers have shown low Aβ42 levels (328.86 ± 99.0 pg/ml) compared to Apo- Eε4 allele non-carriers (367.52 ± 57.37 pg/ml), while tau levels were higher in Apo-Eε4 allele carriers (511 ± 44.67 pg/ml) compared to Apo-Eε4 allele non-carriers (503.75 ± 41.08 pg/ml). Combination of Aβ42 and tau resulted in sensitivity of 75.38% and specificity of 94.82% and diagnostic accuracy of 84.30% for AD compared with the controls. Therefore low Aβ42 and elevated tau concentrations in CSF may prove to be a better diagnostic marker for AD along with the Apo-Eε4 allele.

Vasoactive regulatory and transport proteins can modify the transendothelial blood-brain barrier (BBB) transport of beta-amyloid. Dysfunction of one or more of these proteins is hypothesized to contribute to the pathogenesis of Alzheimer's disease (AD). In this study we investigated superior temporal and occipital cortical sections from ten AD and ten control group brains (CG). They were examined using immunohistochemical techniques staining for β42 amyloid, APOE, VEGF and eNOS. The densities of senile plaques (SPs) and APOE, VEGF and eNOS positive capillaries in each region and in each AD and CG condition were compared using nonparametric statistical analysis. In the AD cases, there were significant negative correlations between APOE positive capillaries and β42 amyloid SPs, and positive correlations between APOE positive capillaries and VEGF and eNOS positive capillaries. These results demonstrate the increased presence of APOE activity in AD brain capillaries, and that there is a positive correlation between the expression of APOE and each of VEGF and eNOS in the capillaries of AD brains. It is possible, therefore, that the down regulation of APOE in AD brains may contribute significantly to the pathogenesis of SP lesion development by modulating brain β- amyloid burden. The specific interrelationship between APOE, VEGF and eNOS activity at the BBB requires further investigation.

Background: EHT0202 (etazolate hydrochloride) is a new compound exhibiting both potential diseasemodifying and symptomatic treatment properties in Alzheimer's Disease increasing alpha-secretase activity and sAPP alpha secretion, as well as acting as a GABA-A receptor modulator and as a PDE-4 inhibitor. Methods: This pilot, randomized, double-blind, placebo-controlled, parallel group, multicentre, Phase IIA study was conducted in 159 randomized patients suffering from mild to moderate Alzheimer's Disease. EHT0202 (40 or 80mg bid) or placebo was administered as adjunctive therapy to one acetylcholinesterase inhibitor over a 3-month period. This study was designed to assess the clinical safety and tolerability of EHT0202 as a primary objective, with secondary endpoints (cognitive function, daily living activities, behaviour, caregiver burden and global functioning) included to explore clinical efficacy of EHT0202 versus placebo. Results: EHT0202 was shown to be safe and generally well tolerated. Dose-dependent numbers of early withdrawal and central nervous system related adverse events were observed. As expected, since the study was not powered and not designed to show drug efficacy, and except for ratings on the ADCS-ADL scale, no significant differences were seen between treatment groups. Conclusions: These first encouraging safety results do support further development of EHT0202 in order to assess its clinical efficacy and to confirm its tolerability in a larger cohort of Alzheimer patients and for a longer period.

Membrane rafts are sterol- and sphingolipid-enriched domains that compartmentalize cellular processes. Membrane rafts isolated from post-mortem AD brain are enriched in both β-amyloid and phosphorylated tau. Proteolytic processing of APP to generate β-amyloid, the principle component of amyloid plaques, can occur in membrane rafts, implicating them in the pathogenesis of Alzheimer's disease (AD). Secondary to their role in β-amyloid generation, membrane rafts have more recently been implicated in the accumulation, aggregation and degradation of β-amyloid, with evidence supporting a specific role for membrane raft gangliosides in the binding and aggregation of β-amyloid. In addition, membrane domain composition has a direct impact on both the generation of β-amyloid and its subsequent toxic actions and as such is a key target for the development of therapeutic strategies. This mini-review will focus on recent advances in our understanding of the relevance of membrane composition, of both raft and non-raft domains, to AD progression in models and in human disease. We will discuss how manipulation of membrane composition can alter both the proteolytic processing of APP and the subsequent binding and aggregation of β-amyloid peptide.