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Table of contents for issues of American Mathematical Monthly Volume 7, Number 1, January, Volume 7, Number 2, February, Volume 7, Number 3, March, . Michael E. Senko A Control System For Logical Block Max Goldstein Significance arithmetic on a digital.
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Importantly, each of these families has a different duplication but the region of overlap contains the APP gene. For example, although the normal function of APP is still not resolved, recent evidence suggests that APP plays a role in axonal pruning and neuronal migration during nervous system development 80 , 81 as well as contributing to certain cognitive behaviors such as learning and memory In particular, an N-terminal cleavage fragment of APP is important for its effects during development on axonal pruning In addition to APP , mutations in 2 other genes have been identified in which specific mutations result in the rare, autosomal dominant forms of FAD: These genes encode highly homologous transmembrane proteins in which multiple mutations have been identified in FAD families http: In these families, the PSEN mutations may not segregate perfectly with disease either because of incomplete penetrance mutation carriers who do not develop disease or because of phenocopies disease not caused by the mutation 86 , A normal function of presenilins is to form a gamma secretase complex with 3 other proteins, APH-1, PEN2, and nicastrin 88 , Notch is a protein involved in cell fate decisions during development and in the adult animals.

PSEN1 knockout mice die in utero and have a very similar phenotype to Notch knockout mice Gamma secretase has been a challenging drug target because of the side-effects resulting from cleavage of other, non-APP substrates such as notch.

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For example, inhibition of Notch cleavage results in toxicities related to altered cell proliferation in the gut, the immune system, and the skin One gamma secretase inhibitor recently made it all the way into a phase III clinical trial in AD; however, the trial was halted due to treated patients worsening cognitively more than placebo-treated patients Whether it will be possible to relatively selectively inhibit cleavage of APP vs. The function of presenilins is required for survival and PSEN1 knockout mice die in the embryonic period due to a variety of developmental defects 98 , , Such an explanation has not been formally ruled out.

Though the clinical phenotypes seen with PSEN mutations have many features similar to LOAD, there are some differences in certain families such as a more rapid course and spinal cord involvement in rare situations Numerous companies have developed BACE inhibitors and several have now entered clinical trials. Certainly, many trials have occurred and are ongoing in people with dementia due to late-onset AD. This will be a challenge given the relatively small number of affected families worldwide though it should offer a unique opportunity to test compounds in people who are relatively young and generally not affected by other concurrent brain disorders seen commonly in the elderly.

These findings have been substantiated in populations around the world. ApoE is an important regulator of plasma lipoprotein metabolism , In addition to expression in the liver, apoE is also produced at high levels within the CNS where it is present in high density lipoprotein HDL -like lipoproteins secreted predominantly by astrocytes Although apoE can play a role in a variety of processes in the CNS including cholesterol transport, neuronal plasticity, and inflammation , its exact function in normal and disease conditions remains to be clarified.

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There are several hypotheses about how apoE may influence AD pathogenesis. Despite hundreds of studies during the last fifteen years, few reported genetic associations have been replicated across studies see www. The main reason for this is that other genetic risk factors have a much smaller impact on risk than that of the APOE genotype. As a result the sample sizes used in these earlier studies were too small to have the power to detect these genes. During the last few years several technological advances have transformed the landscape regarding the genetics of common complex traits such as AD , The first of these was the development of genome-wide arrays that allowed the simultaneous evaluation of millions of single nucleotide polymorphisms SNPs in thousands of samples.

The use of these arrays in thousands of samples from AD cases and non-demented elderly controls has resulted in compelling evidence for a number of new genetic risk factors including association with genes encoding clusterin CLU , phosphatidylinositol-binding clathrin assembly protein PICALM , complement receptor 1 CR1 , bridging integrator protein 1 BIN1 , and sialic acid binding Ig-like lectin CD33 — The functional alleles responsible for each of these associations have yet to be determined. The odds ratio is a measure of effect size , describing the strength of association or non- independence between two binary data values.

Estimates of the population attributable fractions for these new candidate genes are between 2. These new gene discoveries provide new impetus for focused studies aimed at understanding the pathogenesis of AD Table 1. It is also possible that some of the new genetic discoveries are not targeting the nearby gene but actually targeting non-coding RNAs. If so, this could also provide new insights. One possibility is that the SNPs on the GWAS chips do not capture all of the genetic variation associated with AD; another possibility is that variants tagged by SNPs on the chips failed to reach genome-wide significance because the sample size used was insufficient.

The second possibility can be overcome by increasing sample size through meta-analysis. Recent advances in sequencing technology have resulted in a sharp decrease in sequencing costs. Rare sequence variants that cause or increase risk for AD are likely to be found by whole exome and whole genome sequencing. This approach has already proved very effective in identifying causative genes for rare recessive disorders Exome sequencing studies are likely to start soon in families with late-onset AD and will likely lead to the identification of new AD genes in the future.

Though identification of new genes may lead to new insights into AD pathogenesis and new therapeutic targets, it may still be challenging to translate such targets into effective therapies. While APOE is the strongest genetic risk factor for AD, it is still not clear whether and how it can be directly targeted effectively.

Approaches for identifying new risk factors associated with other aspects of the LOAD phenotype are still in their infancy but include genetic studies for elucidating the rate of disease progression; age at onset; CSF or plasma biomarker measurements; and functional and structural imaging measures to mention just a few , An advantage of these quantitative traits is the ability to select individuals from the extremes of the trait distribution.

In another study, SNPs within the PPP3R1 gene, encoding the regulatory subunit of calcineurin, were associated with higher CSF concentrations of tau and phosphorylated tau, and increased tangle pathology In AD cases, the alleles associated with higher CSF tau and phosphorylated tau were also associated with a more rapid disease progression. Genes obviously do not act in a vacuum. However, a major bottleneck has been that relatively little is yet understood about the way genetic and environmental factors combine to moderate or exacerbate the risk for AD. If such interactions can be better understood, it may suggest clearcut ways to alter AD risk in genetically predisposed populations.

A challenge will be to study large number of cognitively normal middle aged individuals with differential genetic risk for AD to determine if common modifiable environmental and genetic factors clearly interact to increase risk. Some such studies are currently underway. Epidemiological studies have demonstrated that age, family history and head injury with loss of consciousness influence risk for AD. Overall, head injury is associated with an odds ratio of around 2 — The mechanisms underlying this interaction is still poorly understood.

APOE genotype was not examined in this study but may combine with education to moderate this effect on cognition. Analyses in human subjects also demonstrate that active individuals who meet the exercise guidelines set by the American Heart Association have significantly less amyloid deposition in the brain In addition, some but not all of the models show varying degrees of behavioral impairment Targeting aspects of neuroinflammation may also be a viable therapeutic approach; however, models with neuroinflammation and aspects of neurodegeneration need to be present in order to determine if altering specific aspects of the neuroinflammatory process truly decrease important aspects of neurodegeneration before moving new therapies into human trials.

Overall, this work suggests that tau aggregation is central to the clinical progression of AD. Tau is a microtubule-associated protein that plays an important role in microtubule stability. It is a major component and a primary constituent of NFTs that are found in AD as well as in a host of other neurodegenerative diseases such as certain frontotemporal dementias and progressive supranuclear palsy Some families with autosomal dominant forms of a non-AD dementia, frontotemporal dementia with Parkinsonism FTDP , have mutations in the tau gene on chromosome 17 — Expression of a mutant form of tau that causes FTDP in transgenic mice results in age-dependent tangle formation in some regions of the CNS as well as significant neuronal loss and neurological impairment , From the genetic standpoint, there are SNPs in the MAPT gene encoding tau as well as in a major tau phosphatase, protein phosphatase B calcineurin , that do not affect risk for AD but affect its progression; tau concentrations in CSF are also markers of neurodegeneration.

The extent to which oligomers, fibrils, or both are toxic in vivo remains unclear. It is not yet clear if this is the case. Some of these molecules are receptors, others are signaling molecules, and some are enzymes. A subset of patients who entered the phase I trial were followed for several years after the trial was halted and their brains were assessed at autopsy.

In several individuals, there was evidence of substantial amyloid clearance from the brain though no there was no obvious halting of clinical disease progression , Since a full clinical trial was not done and even the current results are from an aborted phase I trial that was not powered to assess efficacy, it is difficult to know whether there would have been a clinical effect. Genetic manipulations have shown that in mice that develop tauopathy, turning off the expression of tau even after tangles have developed prevents further brain atrophy and improves behavior , Thus, if tau can be safely and effectively reduced or dephosphorylated at certain sites or its aggregation can be inhibited, this may be an attractive therapeutic approach.

A challenge for the field will be to determine whether tau levels, tau aggregation, and tau phosphorylation can be both targeted effectively and safely. A clinical trial of a tau aggregation inhibitor, methylene blue, is underway and will likely to be one of the first of many attempts to target tau. However, the significant accumulation of NFTs, oxidative stress, inflammation, synaptic and network dysfunction, and ultimately neuronal cell death probably does not peak until the stages of moderate to severe dementia Figure 3. Some tangle development clearly is present in the period prior to clinical onset of AD but the acceleration of tau aggregation and neurodegeneration may mark the transition period just prior to clinically detectable disease.

Clinical trials that take advantage of these advances have not yet taken place, although some are being designed, potentially for implementation in FAD individuals for reviews of recent drug trials and consideration of future trial designs, see , Part of the failure to date of currently tested treatments may be due to the fact that drugs that have completed large phase III trials may not have been effectively hitting their target e.

New methods to assess whether proposed disease-modifying agents are effectively hitting their target are now being incorporated in phase I and II trials in humans , However, because of the time course of AD pathology and neurodegeneration prior to the onset of cognitive symptoms, it would seem critical and a major challenge to determine the best way to do clinical trials in cognitively normal people who are very likely to develop AD. Although it seems intuitive that the earlier one starts with therapy prior to cognitive decline, the more likely an effect will be seen, trials of large numbers of individuals, in the absence of screening techniques, would likely take 10—20 years to fully assess the benefits of treatment and would require very large financial resources.

On the other hand, with current biomarker and genetic information, it is likely feasible to screen individuals greater than 60 years of age and select those at very high risk for cognitive decline over a 3—4 year period with biomarkers. In addition, the study of individuals with preclinical AD due to autosomal dominant mutations such individuals are virtually certain to develop symptomatic AD will define the predictive value of specific biomarkers in this population with the goal of ultimately enabling testing of promising therapies.

In particular, the accumulation and aggregation of tau appears to play a critical role in disease progression. In LOAD, brain injury due to other disorders such as cerebrovascular disease, diabetes, and Lewy body pathology are common and a challenge will also be to mitigate the effects of these processes. There is a great need not only for continued refinement and development of antecedent biomarkers, which identify preclinical AD and increasingly appear to predict dementia due to AD, but also for markers that predict treatment effects for use in future clinical trials.

Such approaches as well as others that prevent or slow neurodegeneration through different mechanisms, including environmental manipulation e. Starting as early as possible prior to the appearance of cognitive symptoms is likely to be a critical strategy to make major headway against this devastating disease. National Center for Biotechnology Information , U. Author manuscript; available in PMC Apr 6.

Morris John , 1, 4, 5, 6 and Alison Goate 1, 2, 5, 6.

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Louis, MO Find articles by C. Holtzman, Washington University, Dept. Louis, MO , ude. The publisher's final edited version of this article is available at Sci Transl Med. See other articles in PMC that cite the published article. Clinical features of AD Dementia is an acquired syndrome characterized by a loss or decline in memory and other cognitive abilities.

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Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord. Use of florbetapir-PET for imaging beta-amyloid pathology. Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer Disease.

Neuropathology of nondemented aging: Oskar Fischer and the study of dementia. Biochemical detection of Ab isoforms: Hardy J, Selkoe DJ. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Immune activation in brain aging and neurodegeneration: The inflammatory response system of brain: Beta-amyloid, blood vessels, and brain function. Anti-amyloid antibodies and inflammatory cerebral amyloid angiopathy.

Cerebral microinfarcts associated with severe cerebral beta-amyloid angiopathy. Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: Structural characterization of the core of the paired helical filament of Alzheimer disease.

Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Abnormal phosphorylation of the microtubule-associated protein tau tau in Alzheimer cytoskeletal pathology. Small SA, Duff K. Davies P, Maloney AJ. Dement Geriatr Cogn Disord. Cochrane Database Syst Rev. Amyloid deposition is associated with impaired default network function in older persons without dementia. Spatial correlation between brain aerobic glycolysis and amyloid-beta Abeta deposition.

A default mode of brain function. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. APP processing and synaptic function. Braak H, Del Tredici K. Frost B, Diamond MI. Prion-like mechanisms in neurodegenerative diseases. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.

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Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Transmission and spreading of tauopathy in transgenic mouse brain. Biochem Biophys Res Commun. Amyloid plaque core protein in Alzheimer disease and Down syndrome.


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Lai F, Williams RS. A prospective study of Alzheimer disease in Down syndrome. Amyloid beta protein gene: Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein precursor. Processing of the amyloid protein precursor to potentially amyloidogenic derivatives.

Amyloid beta-peptide is produced by cultured cells during normal metabolism. Cao X, Sudhof TC. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis Dutch Science. Enhanced pathologic properties of Dutch-type mutant amyloid beta-protein.

Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Pathogenic effects of D23N Iowa mutant amyloid-protein. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor beta APP mutants. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: Visualization of A beta 42 43 and A beta 40 in senile plaques with end-specific A beta monoclonals: APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy.

APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Biochemical and functional interaction of disrupted-in-schizophrenia 1 and amyloid precursor protein regulates neuronal migration during mammalian cortical development. The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice.

Amyloid beta from axons and dendrites reduces local spine number and plasticity. Cruchaga C, Goate AM.

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The role of presenilin cofactors in the gamma-secretase complex. Reconstitution of gamma-secretase activity. Photoactivated -secretase inhibitors directed to the active site covalently label presenilin 1. Please enter your name. The E-mail message field is required. Please enter the message. Please verify that you are not a robot. Would you also like to submit a review for this item? You already recently rated this item. Your rating has been recorded. Write a review Rate this item: Preview this item Preview this item.

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