A unifying hypothesis of Alzheimer's disease. I. Ageing sets the stage

Heininger, Kurt

doi:10.1002/(sici)1099-1077(199908)14:6<363::aid-hup125>3.0.co;2-r

Cited by 13 publications

(3 citation statements)

References 678 publications

(521 reference statements)

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“…Recent investigations of several AN-1792-vaccinated patients, who survived for extended periods, revealed that all ultimately died with dementia despite an apparent therapy-induced absence of amyloid deposits [1]. The factors that both influence or are influenced by APP processing remain undefined, but may include fundamental energy deficiency [71;72;77–79] arising as a consequence of increasing vascular deficiencies [47;49;80], mitochondrial failure [81–84] or other stressing mechanisms and co-morbidities associated with aging decay that, in principle, could exert a broad range of synergistic impacts beyond amyloid deposition.…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein transgenic mouse models and Alzheimer's disease: Understanding the paradigms, limitations, and contributions

Kokjohn

Roher

2009

Alzheimer's & Dementia

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Transgenic (Tg) mice overexpressing mutant familial Alzheimer’s disease (AD) amyloid precursor protein (APP) genes have contributed to the understanding of dementia pathology and support the amyloid cascade hypothesis. Although many sophisticated mice APP models exist, none recapitulates AD cellular and behavioral pathology. The morphological resemblance to AD amyloidosis is impressive, but fundamental biophysical and biochemical properties of the APP/Aβ produced in Tg mice differ substantially from those of humans. The greater resilience of Tg mice to substantial Aβ burdens suggests the levels and forms that are deleterious to human neurons are not as noxious in these models. Tg mice have been widely used for testing AD therapeutic agents and demonstrated promising results. Unfortunately, clinical trials resulted in unforeseen adverse events or negative therapeutic outcomes. The disparity between success and failure is in part due to differences in brain environment that separate man and rodent. These observations suggest that the pathogenesis of AD is by far much more intricate than the straightforward accumulation of Aβ.

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Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein transgenic mouse models and Alzheimer's disease: Understanding the paradigms, limitations, and contributions

Kokjohn

Roher

2009

Alzheimer's & Dementia

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“…However, these techniques have not been particularly useful for pharmacology compared to neurochemical techniques [33], with particular reference to the main neurotransmitters identified [31]. For example, according to Schneider [64], the signs of psychosis associated with dementia are highly correlated to a reduction of serotonin levels in the cortex, a major reduction of the cholinergic neurotransmission (notably in the frontotemporal circuits) and to an increase in the number of adrenoceptors in different areas of the brain.…”

Section: Theoretical Basismentioning

confidence: 99%

Comparative effects of pharmacotherapy on the maintenance of cognitive function

et al. 2001

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The quality of human cognitive performance appears today as one of the main components of quality of life, whatever the age. Ageing by itself and most of the diseases affecting the central nervous system alter higher brain functions such as memory, vigilance and attention. Dementia is the most acute example, with a cascade of behavioral and psychological consequences (BPSD), which are the main cause of the caregiver's burden and need specific pharmacotherapy. In this respect, the problem will be the choice of the best drug in situations such as wandering, agitation, violence, and screaming. The psychotropics, however, should not deteriorate the already disturbed cognition of the patients. This is the reason why we propose to establish for each drug, and notably for the antipsychotics, a precise and exact "cognitive mapping"; in other words, to measure the effects of drugs on the different components of cognition. The results of such studies will be predictive of the future phase III clinical trials and therapeutic responses. As an illustration of this approach we shall relate two studies, TIATEM (phase I) and TIAGE (phase III/IV), leading to the determination of a good cognitive safety profile of an atypical neuroleptic drug, tiapride.

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“…The gonadal hormone-mediated deterioration of the somatic trophic milieu elicits a systemic and cellular metabolic stress response (Heininger 1999). Mitochondria have been shown to be a central key affecting lifespan (Kirkwood and Kowald 1997).…”

Section: Introductionmentioning

confidence: 99%

Review and perspectives of physiological mechanisms underlying genetically-based resistance of the Pacific oysterCrassostrea gigasto summer mortality

Samain

2011

Aquat. Living Resour.

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-French oyster farming has been subject to severe mortalities during the summer months. Results from the research program "Morest", which ran from 2000 to 2006 and examined the possible causes of these mortalities, led to the construction of a model to explain the interaction between environmental factors, oyster physiology and different opportunistic pathogens underlying oyster summer mortality. Temperature, food, reproduction and stress were the main factors required for oyster mortality. Genetically-based resistance ("R" oysters) or susceptibility ("S" oysters) to summer mortality was revealed by divergent selection. Building on these results, a literature search was made in 2007 on the molecular origin of genetic resistance to such a complex mortality risk. The objectives were to lay a foundation for the preparation and orientation of future research directions and to improve understanding of the underlying physiological mechanism leading to summer mortality. Three years later, the resulting conceptual analysis reported here was presented as an introductory lecture to Physiomar 2010, a conference where many new results contributing to this research field were also reported. The literature review highlighted two major review articles: the first dealing with nutrition and reproduction (Schneider 2004), the second with reproduction, temperature, oxidative stress and mortality (Heineinger 2002). The effect of nutrition level on energy orientation to growth or reproduction is controlled by endocrine factors. Among these, neuropeptide Y (NPY), ghrelin and leptin neuropeptides appeared to be potential candidates involved in germ-soma orientation in relation to trophic conditions. Depending on reproductive effort and temperature, a metabolic stress resulting from the germ-soma conflict can appear, characterized by mitochondrial reactive oxygen species (ROS) production. Such an excess of ROS induces perturbations in mitochondrial activity leading to cell death. Many organisms, such as annual plants or the Pacific salmon, do not survive their first reproduction. In contrast, others increase stress resistance by selection of antioxidant processes (superoxide dismutase SOD, catalase, etc.) through evolution, and survive first reproduction. A similar difference was observed in the comparison made between R and S oysters, which differed in ROS production, SOD and catalase levels. Such factors controlling reproduction and ROS detoxification processes could therefore provide new markers for selection of oysters with better resistance to non-specific pathogens, complementing other classic selection approaches against specific pathogens or for improved immunity. This antioxidant defence mechanism is found in many organisms including vertebrates and in some invertebrates, including oysters. Its role needs to be considered in pathology events involving other aquaculture species and it may also contribute to explaining the increase in marine pathologies under anthropogenic environmental changes.

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A unifying hypothesis of Alzheimer's disease. I. Ageing sets the stage

Cited by 13 publications

References 678 publications

Amyloid precursor protein transgenic mouse models and Alzheimer's disease: Understanding the paradigms, limitations, and contributions

Amyloid precursor protein transgenic mouse models and Alzheimer's disease: Understanding the paradigms, limitations, and contributions

Comparative effects of pharmacotherapy on the maintenance of cognitive function

Review and perspectives of physiological mechanisms underlying genetically-based resistance of the Pacific oysterCrassostrea gigasto summer mortality

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