Current Alzheimer Research - Volume 7, Issue 1, 2010

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Alzheimer's disease (AD) is the major cause of dementia in the world. Although the entorhinal cortex and hippocampal complex are best known as the sites of early pathology in AD, increasing evidence shows that the eye, particularly the retina, is also affected. The AD-related changes in the retina are associated with degeneration and loss of neurons, reduction of the retinal nerve fibres, increase in optic disc cupping, retinal vascular tortusity and thinning, and visual functional impairment. Given the fact that evaluating pathologic changes in the brain during life has always been an indirect process, largely shielded from view by the barrier of the skull, the eye can be used as a window into diseases of the brain. Using modern techniques, the changes in the retina can be visualized in real-time. In addition to the changes in the eyes of AD patients, similar mechanisms of neurodegeneration in the brain have also been demonstrated in the eye. Targeting AD-liked changes in the retina has been recently shown to be effective in the reduction of retinal neuronal degeneration and loss in eye diseases. This review will cover recent findings on retinal degeneration in AD, pathological similarities between AD and eye diseases, and highlight the potential of modern technologies for the detection of prospective biomarkers in the eye in early AD.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline with loss of memory. In the last years there has been a great interest on the early phases of AD, trying to identify the pathogenic mechanisms of AD and define early treatment modalities. In particular, Mild Cognitive Impairment (MCI) is attractive because it represents a transitional state between normal aging and dementia, although not all MCI patients automatically convert to AD. The neurotrophin brain-derived neurotrophic factor (BDNF) is critical for survival and function of neurons that degenerate in AD and represents a potential neuroprotective agent. However, opposite data on serum levels of BDNF have been reported in AD patients, probably reflecting differences in patient recruitment and stage of the disease. Thus, in this study we measured BDNF serum levels in AD patients (with different degree of severity), MCI patients and healthy subjects. We found that serum BNDF levels were significantly increased in MCI and AD patients when compared to healthy subjects and this increase in AD patients was neither dependent on illness severity, nor on treatment with Acetylcholinesterase inhibitors and/or antidepressant medications. Our findings indicate that BDNF serum levels increase in MCI and AD patients, supporting the hypothesis of an upregulation of BDNF in both preclinical phase of dementia (MCI) and clinical stages of AD. Other studies are necessary to establish a direct link between BDNF peripheral levels and AD longitudinal course, as well as the role of other factors, such as blood cell activation, in determining these events.

Alzheimer's disease (AD) is an insidious and progressive disease with a genetically complex and heterogenous etiology. More than 200 fully penetrant mutations in the amyloid β-protein precursor (APP), presenilin 1 (or PSEN1), and presenilin 2 (PSEN2) have been linked to early-onset familial AD (FAD). 177 PSEN1 FAD mutations have been identified so far and account for more than ∼80% of all FAD mutations. All PSEN1 FAD mutations can increase the Aβ42:Aβ40 ratio with seemingly different and incompletely understood mechanisms. A recent study has shown that the 286 amino acid N-terminal fragment of APP (N-APP), a proteolytic product of β-secretase-derived secreted form of APP (sAPPβ), could bind the death receptor, DR6, and lead to neurodegeneration. Here we asked whether PSEN1 FAD mutations lead to neurodegeneration by modulating sAPPβ levels. All four different PSEN1 FAD mutations tested (in three mammalian cell lines) did not alter sAPPβ levels. Therefore PS1 mutations do not appear to contribute to AD pathogenesis via altered production of sAPPβ.

Elevated amyloid-β peptide (Aβ) and loss of nicotinic acetylcholine receptors (nAChRs) stand prominently in the etiology of Alzheimer's disease (AD). Since the discovery of an Aβ - nAChR interaction, much effort has been expended to characterize the consequences of high versus low concentrations of Aβ on nAChRs. This review will discuss current knowledge on the subject at the molecular, cellular, and physiological levels with particular emphasis on understanding how Aβ - nAChR interaction may contribute to normal physiological processes as well as the etiology of AD.

Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of β-amyloid (Aβ) peptides may cause Alzheimer's disease (AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting Aβ have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating Aβ clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Aβ monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating Aβ formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases, β-secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of β-secretase, the protease that regulates the last metabolic step generating Aβ, have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate β-secretase, the enzyme responsible for the nonamyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of Aβ aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-Aβ approaches in clinical testing, we will know in few years if the Av hypothesis of AD is correct.

Background: New in vivo amyloid PET imaging tracers, such as 11C-PIB, provide possibilities to deeper understand the underlying pathological processes in Alzheimer's disease (AD). In this study we investigated how 11C-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 11C-PIB, 18F-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-ß (Aβ1-42), 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 11C-PIB retention, levels of CSF biomarkers (especially Aß1-42), rCMRglc and episodic memory. Analysis of the MCI group alone revealed significant correlations between 11C-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 11C-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. 11C-PIB PET and CSF Aß1-42 allowed detection of prodromal stages of AD. Amyloid imaging is useful for early diagnosis and evaluation of new therapeutic interventions in AD.

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 effects 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) is 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.

The whole set of the so-called « conformational» disorders, among them systemic amyloidoses, various dementias and other neurodegenerative diseases such as Parkinson's, Alzheimer's and amyotropic lateral sclerosis, may have similar molecular backgrounds: changes in protein conformation and aggregation, which lead to toxic amyloid oligomers and fibrils. The so called aggresomes in eukaryotes (equivalent to inclusion bodies in prokaryotes), located at the centriole by the nucleus and composed of aggregated proteins, are believed to sequester the toxic material. They eventually get cleared from the cell by autophagy. When the cell defense system fails due to continuous production of a mutated protein or to other damage to the cell, such as oxidative stress or protein modification as part of normal aging, familial or sporadic neurodegenerative diseases develop. Initially - for years - they are silent with no or mild symptoms. It could well be that aggregates represent a response to some other trigger or even a means of defense. However, the inherited cases with mutations leading to increased aggregation suggest the opposite to be the case. Evidence has accumulated that the soluble oligomers of amyloidogenic proteins are themselves cytotoxic and trigger a cascade of detrimental events in the cell, as summarized in the “amyloid cascade hypothesis”. Among other plausible hypotheses for the mechanism of toxicity is the “channel hypothesis”, which states that the soluble oligomers interact with cell membranes, causing influx of Ca2+ ions, which is an early sign of pathology and contributes to uncontrolled neurotransmission. Another factor are metal ions, such as Zn2+, Cu2+, Fe3+, Al3+, etc., leading to the “metal hypothesis”. The delicate balance of metal ions in the brain is important to prevent oxidative stress, which can itself modify proteins and make them aggregation-prone. The advances in molecular and cellular studies will hopefully lead to novel therapies and eventually to a cure.

CA3 pyramidal neurons and hilar mossy neurons possess large and branched dendritic spines, named thorny excrescences. Studies on experimental animals have shown great morphologic adaptation of the excrescences and the whole dendritic tree of CA3 pyramidal neurons in changes of environmental conditions. However, the available data about the excrescences in human brain is short and insufficient about their properties in Alzheimer's disease. In the present study, these dendritic structures were studied and compared in CA3 area of hippocampus in patients suffered from Alzheimer’s disease, age matched controls and young individuals. Golgi impregnated material under light microscopy was used for the description of the structural characteristics of the excrescences. Morphometric estimation of their density on the apical and basilar dendritic tree and their average length revealed reduced density and significantly increased size in Alzheimer's disease patients. The mean density of the excrescences on the apical dendritic tree of the patients compared to age matched controls is reduced 32.8% (p< 0.001), while the mean number of long excrescences (longer than 5μm) is increased 32.6% (p< 0.05). On the basilar dendritic tree, the reduction in density is 26.3% (p< 0.05) and the increase in the number of long excrescences is 23.3% (p> 0.05). These enlarged thorny excrescences can be even longer than 10μm, appearing as “giant spines”. The increased size of the excrescences is considered as a remodeling procedure (compensative mechanism) of the CA3 pyramidal neurons for the balancing of the reduction in the spinal density.

Results from clinical samples suggest low serum albumin may be associated with cognitive impairment, though evidence from population-based studies is inconclusive. Participants were 1,752 adults (699 men and 1,053 women) aged 65 years and over from the Health Survey for England 2000, a nationally representative population-based study. Cognitive impairment was assessed using the Abbreviated Mental Test Score. The cross-sectional relation of serum albumin quartiles to cognitive impairment was modelled using logistic regression. Two hundred and twelve participants were cognitively impaired (68 men and 144 women). Odds ratios (95% confidence intervals) for cognitive impairment in the first (2.2-3.8 g/dl), second (3.9-4.0 g/dl), and third (4.1-4.3 g/dl) quartiles of serum albumin compared with the fourth (4.4-5.3 g/dl) were 2.5 (1.3-5.1), 1.7 (0.9-3.5), and 1.5 (0.7-2.9), after adjustment for age, sex, education and additional risk factors for cognitive impairment (p for linear trend = 0.002). A highly similar pattern of associations was observed for men and women. Our data provide new evidence to suggest that low serum albumin is independently associated with increased odds of cognitive impairment in the elderly population.