Current Alzheimer Research - Volume 2, Issue 4, 2005

Neuronal loss is associated with Alzheimer's disease (AD). However, it not clear what type of mechanisms underlie this neuronal loss and if neuronal loss is directly responsible for the progressive dementia of AD. This review summarizes the recent evidence for neuronal loss in AD relative to the level of cognitive impairment. It further describes the current evidence for an apoptotic mechanism in AD. Lastly, a summary of the evidence for synaptic loss being responsible for dementia rather than neuronal loss is presented. A novel hypothesis emerges from this data to explain all aspects of AD pathophysiology. This all inclusive hypothesis called the attrition hypothesis states that activation of the effector caspase-6 in AD due to one or a variety of insults is responsible for the breakdown of the cytoskeletal structure of neurites and damages proper trafficking of proteins and organelles thus resulting in the observed clinical and pathological features of AD.

The complex nature and genesis of oxidative damage in Alzheimer disease can be partly answered by mitochondrial and redox-active metal abnormalities. By releasing high levels of hydrogen peroxide, dysfunctional mitochondria propagate a series of interactions between redox-active metals and oxidative response elements. In the initial phase of disease development, amyloid-β deposition and hyperphosphorylated t may function as compensatory responses and downstream adaptations to ensure that neuronal cells do not succumb to oxidative injuries. However, during the progression of the disease, the antioxidant activity of both agents evolves into pro-oxidant activity representing a typical gain-offunction transformation, which can result from an increase in reactive species and a decrease in clearance mechanisms.

In order to have more specific tools available to approach amyloidogenesis in Alzheimer's disease (AD), we have produced several polyclonal and monoclonal antibodies that recognize specific sequences of the amyloid β (Aβ) peptide. Here we present results that demonstrate that our monoclonal antibody EM5 recognizes an internal sequence (residues 11-16) of the Aβ peptide. This strategic localization of the epitope allowed us to employ this antibody, together with two previously reported polyclonal antibodies (EM2 and EM3, specific for AβX-40 and AβX- 42, respectively), in an immunohistochemical study aimed at exploring the differential distribution of longer (AβX- 40/42) and shorter (Aβ17-X) peptides along the various types of amyloid deposits of AD. This antibody panel was used in six AD brains, on sections from associative neocortex, striatum and cerebellar cortex. Single and double immunostaining revealed specific staining of vascular amyloid deposits and neuritic plaques by EM5 antibody, with high co-localization of EM2. Our results suggest that EM5 antibody recognizes pathogenic forms of Ab deposits (amyloid angiopathy and neuritic plaques) and reveals the existence of a subset of plaques with a profile similar to vascular deposits. Additionally, our results show that diffuse plaques in AD brains may contain Aβ17-X peptides as its principal component. EM5 may be a useful tool in research both on human and transgenic mice tissue that may aid in the study of molecular heterogeneity of plaques in AD.

The role of polysaccharides in the pathogenesis of Alzheimer disease (AD) is unclear. However, in light of studies indicating impaired glucose utilization in AD and increased activation of the hexosamine pathway that is seen with hyperglycemia, in the brains of patients with AD, aberrantly high levels of glucosamine may result in synthesis of glucosamine polymers such as chitin, a highly insoluble polymer of N-acetyl glucosamine, linearized by b1-4 linkages. To examine this further, we studied brain tissue at autopsy from subjects with sporadic and familial AD using calcofluor histochemistry. Calcofluor excites on exposure to ultraviolet light and exhibits a high affinity for chitin in vivo by interacting with b1-4 linkages. Amyloid plaques and blood vessels affected by amyloid angiopathy showed bright fluorescence. Moreover, treatment with chitinase, followed by b-N-acetyl glucosaminidase showed a decrease in calcofluor fluorescence. Since chitin is a highly insoluble molecule and a substrate for glycan-protein interactions, chitin-like polysaccharides within the brain could facilitate nucleation of amyloid proteins in various amyloidoses including AD.

Semantic memory deficits are a common landmark in Alzheimer's disease, but the nature of these impairments remains to be clarified. The tests used to explore this memory system are not specific and involve cognitive processes often disturbed in Alzheimer's disease. A complementary way to investigate semantic memory in neuropsychology is by using the semantic priming paradigm. Here, semantic priming refers specifically to the modification of a stimulus processing behind the presentation of a related stimulus; it is a short-lived phenomenon considered an implicit measure of semantic memory integrity. However, semantic priming studies have yielded contradictory results in Alzheimer's disease, with authors reporting normal priming, less-than-normal priming, or increased priming effects (hyperpriming). The aim of this paper is to review the literature investigating semantic priming in Alzheimer's disease, and to discuss the contradictory results in the context of current models of semantic processing. For a clear comprehension of the semantic priming patterns in this pathology, we will precise the methodology used and the characteristics of the Alzheimer's disease patients examined. Besides, the surprising hyperpriming phenomenon - often observed in Alzheimer's disease at the early stage of dementia - will also be explained in detail. These results from semantic priming represent invaluable clues to widen our knowledge and conceptions about deterioration of the semantic memory in Alzheimer's disease.

In this paper, we present an illustrative case of Semantic Dementia (SD) and we review the literature on this relatively rare progressive neurodegenerative disorder. After reviewing the clinical, neuroimaging, neuropathological, and genetic features of SD, we propose a theoretical framework that addresses features of SD and relates them to features of other well known neuropsychiatric syndromes. Our 'on-line / off-line disconnection' model seeks to conceptualize SD as a syndrome of disconnection between two large distributed cortical networks, namely, between those networks that subserve language function and those that subserve memory function.

From a clinical as well as a neuropathological point of view Alzheimer's disease (AD) has been the focus of intense research for more than three decades. Most studies to identify morphometric correlates with the declining cognitive function in normal aging and AD have employed semi-quantitative methods to assess neuropathological markers such as neurofibrillary tangles, senile plaques, neuronal, or glial cell densities, and neuron sizes. To this end, many cell counting methods have employed two-dimensional designs in single sections, yielding estimates of cell numbers either as neuron densities (number of cell profiles per area) or estimates of the size distribution of neuron profiles in columns vertical to the cortical surface. This approach gives rise to difficulties in interpretation because of the three-dimensional size, shape, and orientation of the counted cells, and the effect of shrinkage artifacts. Modern stereological techniques offer a more rigorous approach for quantifying neuropathological changes associated with aging and degenerative disease. However the stereological studies also suffer from the limitations of high biological variability in AD-type neuropathology, and the relative scarcity of autopsied brains from well-studied non-demented comparison subjects. As a result, the clinicopathological associations between neuropathology and indices of cognitive performance in aging and AD are not yet firmly established. The requirement for the proper description of morphologic neuropathology of AD is clear: any macroscopic or microscopic abnormalities, are subtle and must consequently be demonstrated reproducibly in well-controlled studies. In this review we try to evaluate which, if any, of the contemporary claims for morphometric brain abnormalities in AD can be said to be well established, with special emphasis placed on human stereological post-mortal studies.

Objective: To evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of the acetyl-selective anticholinesterase, phenserine tartrate, in healthy elderly subjects. Methods: 32 healthy elderly volunteers received single oral doses of phenserine tartrate (5-20 mg). Physical and vital signs were monitored over the ensuing 24 hours. Analyses were performed on plasma samples to determine PK, and PD were assessed using an erythrocyte acetylcholinesterase (AChE) inhibition assay. Results: No serious adverse events (AEs) occurred; the most common were headache and vomiting. The MTD of phenserine tartrate was 10 mg. The Cmax and AUC(0-24) of phenserine increased with dose, but neither were doseproportional. Subjects receiving 10 mg of phenserine tartrate had a Cmax of 1.95 ng/mL at 1.5 hours, and the mean peak inhibition (Imax) of AChE was 26% (range: 18-34%) at 1.75 hours (tImax) following dosing. The half-life of AChE inhibition (tI1/2) was 11 hours. Evaluation of PK/PD relationships suggested a linear correlation between plasma phenserine concentration and AChE inhibition in the blood. Conclusions: Phenserine tartrate was safe and well tolerated when administered as a single oral dose of either 5 mg or 10 mg. An increase in the severity and frequency of AEs occurred at the 20 mg dose level.