The future of Alzheimer's disease: The next 10 years

Hampel, Harald; Prvulovic, David; Teipel, Stefan J.; Jessen, Frank; Luckhaus, Christian; Frölich, Lutz; Riepe, Matthias W.; Dodel, Richard; Leyhe, Thomas; Bertram, Lars; Hoffmann, Wolfgang; Faltraco, Frank

doi:10.1016/j.pneurobio.2011.11.008

Cited by 194 publications

(149 citation statements)

References 107 publications

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“…Future studies are needed to determine the efficacy of MRI to detect AD type pattern of atrophy in the presence of comorbidities that had usually been excluded in studies so far. In addition, the effect of a novel structural imaging marker of predementia AD on care systems worldwide that have difficulties to provide adequate care even to patients in clinically manifest stages of disease needs to be assessed in future studies [4].…”

Section: Future Directions: Application Of Existing Methods In a New mentioning

confidence: 99%

“…A mono-linear amyloid cascade perspective, would seem reductionistic, since it fails to recognize the role of the many conformations that the proteins may adopt, explaining the progression of the disease through the connections and the transmissibility of the pathology in some experimental conditions. Therefore, in the advent of the worldwide AD epidemic, critical reassessment of the evidence-based significance and limitation of prevailing as well as of emerging fundamental concepts of AD pathophysiology seems to be necessary to foster breakthrough advances to effectively detect, treat or even prevent AD [4]. The search for biomarkers of preclinical AD is becoming increasingly important because pathogenesis-targeted neuroprotective strategies are being developed for future use in ''at risk'' populations.…”

Section: Introductionmentioning

confidence: 99%

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Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Hampel

Lista

Teipel

et al. 2014

Biochemical Pharmacology

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102

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Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD

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Section: Future Directions: Application Of Existing Methods In a New mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Hampel

Lista

Teipel

et al. 2014

Biochemical Pharmacology

Self Cite

102

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“…Indeed, most neurological and neurodegenerative disorders involve synaptic malfunction that can be linked to abnormalities in AMPARs 142 . For example, one of the earliest cell biological manifestations of dementia in Alzheimer's disease (AD) is reduced synaptic AMPARs, and aberrations in LTP and LTD 143 .…”

Section: Ampar Subunits and Diseasementioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. PrefaceAMPARs are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity, and in response to neuronal stress in disease. Recently, the subunit-dependence of AMPAR trafficking has been questioned leading to a reappraisal of the field. Here we review what is known, uncertain, conjectured and unknown about the roles of individual subunits and how they impact on AMPAR assembly, trafficking and function under normal and pathological conditions. IntroductionAMPA receptors (AMPARs) are a subtype of ionotropic glutamate receptors that are the 'work-horses' of fast excitatory neurotransmission in the CNS. Developmentallyand activity-regulated changes in the numbers and properties of AMPARs localized at the postsynaptic membrane are essential for excitatory synapse formation, stabilization, synaptic plasticity and neural circuit formation. Consequently, the logistics of the delivery, retention and removal of individual AMPARs with defined subunit compositions at specific synapses is highly complex. A typical cortical or hippocampal pyramidal neuron contains on the order of 10,000 synapses and the AMPARs at each synapse are independently and dynamically regulated in response to developmental cues, synaptic activity and environmental stresses. Furthermore, defects in the processes that control AMPAR assembly, trafficking and synaptic expression are intimately linked to psychiatric and neurological conditions, and also with cognitive decline in neurodegenerative diseases. Remarkable progress has been achieved in understanding how AMPAR trafficking, is orchestrated by a large array of AMPAR interacting proteins. These studies have established a set of hierarchical subunit-specific rules that control AMPAR trafficking under basal and activity-dependent conditions. Furthermore, there has been a growing appreciation that subunit composition can tune the properties of AMPARs to specific conditions. Nonetheless, how AMPARs comprising different subunits are differentially trafficked to control synaptic development, stabilisation and plasticity is a key unanswered question. Here, we provide an overview of the current state of knowledge of subunit-specific AMPAR trafficking and outline what we believe to be the key unresolved questions in the field. 2 Subunit-specific traffickingMost AMPARs are heterotetrameric assemblies of combinations of the subunits GluA1, GluA2, GluA3 and GluA4. AMPARs are expressed in both neurons and glia throughout the CNS 1 and have a turnover time of between 10 hours and 2 days depending on the type of neuron and developmental stage 2,3 . Each subunit has an identical membrane topology and c...

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“…Alzheimer's disease (AD) is the leading cause of dementia in aging adults, which currently has about 36 million cases worldwide [1,3,14]. Alzheimer's disease causes a large loss in brain weight and volume and affects some brain regions and neuronal populations [24,36].…”

Section: Introductionmentioning

confidence: 99%

Ciliary neurotrophic factor protects SH-SY5Y neuroblastoma cells against Aβ 1-42 -induced neurotoxicity via activating the JAK2/STAT3 axis

Wang¹,

Xie²,

Zhu³

et al. 2015

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A b s t r a c t The neurotoxicity of aggregated amyloid beta (Aβ) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease (AD), which leads to neuronal cell damage by inducing oxidative stress and consequently triggering cell apoptosis. Recently, Aβ-dependent inactivation of the Janus tyrosine kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway was found to play a critical role in the memory impairment related to AD. Previous research indicated that JAK2/STAT3 axis inactivation might be the result of aberrant reactive oxygen species (ROS) generation induced by Aβ in neurons. As the JAK2/STAT3 axis is a major transducer of ciliary neurotrophic factor (CNTF)-

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The future of Alzheimer's disease: The next 10 years

Cited by 194 publications

References 107 publications

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Synaptic AMPA receptor composition in development, plasticity and disease

Ciliary neurotrophic factor protects SH-SY5Y neuroblastoma cells against Aβ 1-42 -induced neurotoxicity via activating the JAK2/STAT3 axis

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