The cloning of APP and genetic analysis of families with Alzheimer's disease were both reported in 1987 and much present work on the disease is based upon the foundations laid at that time. Progress ...was not smooth, however, and many errors were made. In this memoir, I lay out both the progress and the errors.
Mutations in the amyloid precursor protein (APP) or its processing pathways that lead to deposition of amyloid β peptide in the brain are now accepted as a causative agent of Alzheimer's disease (AD). In this Discovery‐in‐Context Review, John Hardy recounts the early search for the genetic basis of AD, the discovery of mutations in the APP gene and the subsequent formulation of the amyloid cascade hypothesis.
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The amyloid hypothesis has been the basis for most work on the pathogenesis of Alzheimer's disease. Recent clinical trials based on this hypothesis have been inconclusive. In this article I review ...the current status of the hypothesis and suggest that a major scientific need is to understand the normal function of amyloid-β precursor protein (APP) and think how this may relate to the cell death in the disease process.
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On the 100
th anniversary of Alzheimer's lecture describing the clinicopathological entity which bears his eponym, this article reviews the major areas of progress in our understanding of the disease ...and outlines the many gaps still remaining. The progress toward effective mechanistic therapy is reviewed.
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Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and ...clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
This review by Selkoe and Hardy provides a comprehensive and commanding analysis on the causative role of Abeta and the amyloid cascade hypothesis in the pathology of Alzheimer's disease.
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Metallosupramolecular grid complexes (hereafter referred to as metallogrids) are well-defined oligonuclear metal ion complexes involving essentially planar arrays of the metal ions sited at the ...points of intersection of square or rectangular metallogrids and possess a variety of interesting optical, electronic, magnetic and supramolecular properties. Herein I aim to give the reader an overview of the synthesis, properties and potential for a variety of high-tech applications of metallogrids.
Metallosupramolecular grid complexes (hereafter referred to as metallogrids) are well-defined oligonuclear metal ion complexes involving essentially planar arrays of the metal ions sited at the points of intersection of square or rectangular metallogrids and possess a variety of interesting optical, electronic, magnetic and supramolecular properties.
The acute and long-term consequences of traumatic brain injury (TBI) have received increased attention in recent years. In this Review, we discuss the neuropathology and neural mechanisms associated ...with TBI, drawing on findings from sports-induced TBI in athletes, in whom acute TBI damages axons and elicits both regenerative and degenerative tissue responses in the brain and in whom repeated concussions may initiate a long-term neurodegenerative process called dementia pugilistica or chronic traumatic encephalopathy (CTE). We also consider how the neuropathology and neurobiology of CTE in many ways resembles other neurodegenerative illnesses such as Alzheimer’s disease, particularly with respect to mismetabolism and aggregation of tau, β-amyloid, and TDP-43. Finally, we explore how translational research in animal models of acceleration/deceleration types of injury relevant for concussion together with clinical studies employing imaging and biochemical markers may further elucidate the neurobiology of TBI and CTE.
The acute and long-term consequences of traumatic brain injury (TBI) have received increased attention in recent years. In this Review, Blennow et al. discuss the neuropathology and neural mechanisms associated with TBI and consider how these mechanisms resemble other neurodegenerative illnesses.
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Genomewide association studies have uncovered many genetic variants that confer susceptibility to disease. This article describes the genomewide association study and new approaches that may address ...some of its limitations.
Genomewide association studies have uncovered many genetic variants that confer susceptibility to disease. This article describes the genomewide association study and new approaches that may address some of its limitations.
For 20 years, genetic linkage combined with positional cloning has offered a rational and increasingly straightforward route to finding gene mutations that lead to monogenic disease, such as cystic fibrosis and Huntington's disease (see the Glossary). With a few important exceptions, these searches have led to mutations that alter the amino acid sequence of a protein and that enormously increase the risk of disease.
During the past few years, genomewide association studies have identified a large number of robust associations between specific chromosomal loci and complex human disease, such as type 2 diabetes and rheumatoid arthritis
1
(Figure 1). This approach . . .
As we identify the loci involved in late onset neurodegenerative disease, we are finding that the majority of them are involved in damage response processes. In this short review, I propose that it ...is partly a failure in these damage response processes which underlie late onset disease and that the resultant pathology is a marker of the type of damage response which has failed: microglial clearance of damaged neuronal membranes in Alzheimer's disease (AD), ubiquitin proteasome clearance in the tauopathies, and lysosomal clearance in Parkinson's disease (PD). In this review, I outline this relationship. This article is not intended as a comprehensive review of the cell biology of any of these disorders but rather a summary of the evidence that the genetics and pathology of these disorders appear to point, in each case, to the removal of misfolded proteins as a critical process in disease pathogenesis.
Genetic discoveries underlie the majority of the current thinking in neurodegenerative disease. This work has been driven by the significant gains made in identifying causal mutations; however, the ...translation of genetic causes of disease into pathobiological understanding remains a challenge. The application of a second generation of genetics methods allows the dissection of moderate and mild genetic risk factors for disease. This requires new thinking in two key areas: what constitutes proof of pathogenicity, and how do we translate these findings to biological understanding. Here we describe the progress and ongoing evolution in genetics. We describe a view that rejects the tradition that genetic proof has to be absolute before functional characterization and centers on a multi-dimensional approach integrating genetics, reference data, and functional work. We also argue that these challenges cannot be efficiently met by traditional hypothesis-driven methods but that high content system-wide efforts are required.
The piece by Singleton and Hardy describes the evolution and future of the identification and interpretation of genetic influences in neurodegenerative disease. It argues that maximizing the benefits of genetic progress requires a systematic and system wide approach to pathobiology.
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