A Century of Scientific and Clinical Research [M-Q]

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Eliezer Masliah, Leslie Crews, Lawrence Hansen
Synaptic remodeling during aging and in Alzheimer’s disease
Abstract: Cognitive functioning is dependent on synapse density in the brain. Factors modulating synapse density might include the balance between synaptic pruning and sprouting. Loss of synapses during aging might explain cognitive decline and while previous reports have suggested a 10-15% synapse loss occurs during the normal aging process, more recent studies have found that decline in synaptic density only occurs after 65 years of age. In this context, the main objective of this manuscript is to discuss the findings of our 1993 study in light of more recent studies in aging, synapses and Alzheimer’s disease.

Colin L Masters, Konrad Beyreuther
Pathways to the discovery of the Aβ amyloid of Alzheimer's disease
Abstract: Many participants played a role in discovering the composition and sequence of the Aβ amyloid of Alzheimer's disease. This sequence enabled the cloning of the amyloid precursor protein (APP), which elucidated its proteolytic origin from the membrane of neurons. The proteolytic enzymes which process APP and the Aβ fragment itself are now the prime validated drug targets for therapeutic intervention.

Patrick L. McGeerJoseph Rogers, Edith G. McGeer
Inflammation, Antiinflammatory Agents and Alzheimer Disease: The Last 12 Years
Abstract: Two basic discoveries have spurred research into inflammation as a driving force in the pathology of Alzheimer disease (AD). The first was the identification of activated microglia in association with the lesions. The second was the finding that rheumatoid arthritics were relatively spared from the disease. These findings spurred the first pilot trial of a classical NSAID in the treatment of AD. This trial showed promise for indomethacin as a useful therapeutic agent but appropriate follow up trials have not been done. However, more than 20 epidemiological studies have since been conducted showing a sparing effect for antiinflammatories in AD, including four which specifically addressed the use of classical NSAIDs. Other key findings linking inflammation to AD pathology are the identification of activated complement fragments, including the membrane attack complex, as well as inflammatory cytokines in association with the lesions. In vitro, activated microglia release factors which are toxic to neurons, and these can be partially blocked by NSAIDs. Future directions should include a search for other inflammatory mediators in AD and exploitation of current knowledge to improve available treatments.

Ian G. McKeith
Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop
Abstract: Dementia with Lewy bodies (DLB) was considered to be an uncommon cause of dementia until improved neuropathological staining methods for ubiquitin were developed in the late 1980’s. Subsequent recognition that 10-15% of dementia cases in older people were associated with Lewy body pathology led to the publication in 1996 of Consensus clinical and pathological diagnostic criteria for the disorder. These have greatly raised global awareness of DLB and helped to generate a body of knowledge which informs modern clinical management of this pharmacologically sensitive group of patients. They have also enabled important issues surrounding the relationships of DLB with Alzheimer’s disease and Parkinson’s disease to be addressed and partially resolved. A recent re-evaluation of the Consensus criteria has confirmed many aspects of the original recommendations, supplementing these with suggestions for improved pathological characterisation, clinical detection and management. Virtually unrecognised 20 years ago, DLB could within this decade be one of the best characterised and potentially treatable neurodegenerative disorders of late life.

Dave Morgan
Immunotherapy for Alzheimer's Disease
Abstract: A primary goal of research on Alzheimer's disease is to develop disease modifying therapeutics. The amyloid cascade hypothesis has focused the initial efforts on methods to reduce amyloid. One surprising approach that has shown considerable success in mouse models and has hinted at benefits in human trials is anti-Aß immunotherapy. Schenk first showed the amyloid reducing potential of active immunization in 1999. This prompted our group and that of St. George-Hyslop to investigate whether active immunization would similarly retard the memory deficits that develop in amyloid depositing transgenic mice. Contrary to our initial predictions of premature memory dysfunction due to inflammation, vaccination protected amyloid depositing mice from developing memory deficits. Subsequent studies found that passive immunization could reverse memory deficits, even when administered for short periods. These encouraging findings led to a trial of an Aß vaccination in Alzheimer patients. The trial was cut short due to meningoencephalitic symptoms in 6% of patients, yet, in a subset of patients, those developing brain reactive antibodies benefited from slower rates of cognitive decline. These observations have accelerated the development of passive immunization protocols and safer vaccines. At this time, anti-amyloid immunotherapy stands poised to be the first test of the amyloid hypothesis in the treatment of Alzheimer disease.

Ralph A. Nixon, Anne M Cataldo
Lysosomal System Pathways: Genes to Neurodegeneration in Alzheimer’s Disease
Abstract: The identification of cathepsins in amyloid-ß plaques revealed broad dysfunction of the lysosomal system in Alzheimer’s disease (AD). Coinciding with the discovery that proteolysis is required to generate the Aß-peptide, these findings heralded an era of intense investigation on proteases in neurodegeneration. This review traces lysosomal system pathology from its early characterization to its origins within two pathways leading to the lysosome, the endocytic and autophagic pathways. An understanding has grown about how these two pathways are adversely influenced by normal brain aging and by genetic and environmental risk factors for AD, resulting in lowered resistance of neurons to injury, amyloidogenesis, and neurodegeneration.

Daniel P. Perl, Sharon Moalem
Aluminum and Alzheimer’s Disease, A Personal Perspective After 25 Years
Abstract: It is now 25 years since the publication of our original paper investigating the association aluminum with Alzheimer’s disease. This publication reported on the results of scanning electron microscopy coupled x-ray spectrometry microprobe elemental studies of both neurofibrillary tangle-bearing and tangle-free neurons in the hippocampus of cases of Alzheimer’s disease and controls. Peaks related to the presence of aluminum were consistently detected within the tangle-bearing neurons. This paper supported the association of aluminum and Alzheimer’s disease on the cellular level of resolution and caused considerable interest and discussion. Subsequent work demonstrated prominent evidence of aluminum accumulation in the tangle-bearing neurons of cases of amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. This latter observation has now been replicated using five different forms of microanalysis. Finally, using laser microprobe mass analysis, we demonstrated that the abnormally high aluminum-related signal which we originally detected was actually located within the neurofibrillary tangle, itself, and was accompanied by excess concentrations of iron. Although it is unlikely that aluminum represents an etiologic cause of Alzheimer’s disease, we believe that this highly reactive element, known to cross-link hyperphosphorylated proteins, may play an active role in the pathogenesis of critical neuropathologic lesion in Alzheimer’s disease and other related disorders.

George Perry
Solving the insoluble
Abstract: Dissection of neurofibrillary tangles has been confounded by the insolubility of their fibers. While the majority of biochemical studies have considered τ filaments equivalent to neurofibrillary tangles, they forget that the former are soluble and the latter completely resistant to solvents. What, then, accounts for the insolubility of neurofibrillary tangles while τ filaments are soluble? Investigation of these distinctions played a critical role in our findings on proteolytic abnormalities and oxidative stress.