Intranasal “painless” Human Nerve Growth Factors Slows Amyloid Neurodegeneration and Prevents Memory Deficits in App X PS1 Mice

Nerve Growth Factor (NGF) is being considered as a therapeutic candidate for Alzheimer's disease (AD) treatment but the clinical application is hindered by its potent pro-nociceptive activity. Thus, to reduce systemic exposure that would induce pain, in recent clinical studies NGF was administered through an invasive intracerebral gene-therapy approach. Our group demonstrated the feasibility of a non-invasive intranasal delivery of NGF in a mouse model of neurodegeneration. NGF therapeutic window could be further increased if its nociceptive effects could be avoided altogether. In this study we exploit forms of NGF, mutated at residue R100, inspired by the human genetic disease HSAN V (Hereditary Sensory Autonomic Neuropathy Type V), which would allow increasing the dose of NGF without triggering pain. We show that “painless” hNGF displays full neurotrophic and anti-amyloidogenic activities in neuronal cultures, and a reduced nociceptive activity in vivo. When administered intranasally to APPxPS1 mice ( n = 8), hNGFP61S/R100E prevents the progress of neurodegeneration and of behavioral deficits. These results demonstrate the in vivo neuroprotective and anti-amyloidogenic properties of hNGFR100 mutants and provide a rational basis for the development of “painless” hNGF variants as a new generation of therapeutics for neurodegenerative diseases

Case based reasoning as a model for cognitive artificial intelligence.

Cognitive Systems understand the world through learning and experience. Case Based Reasoning (CBR) systems naturally capture knowledge as experiences in memory and they are able to learn new experiences to retain in their memory. CBR's retrieve and reuse reasoning is also knowledge-rich because of its nearest neighbour retrieval and analogy-based adaptation of retrieved solutions. CBR is particularly suited to domains where there is no well-defined theory, because they have a memory of experiences of what happened, rather than why/how it happened. CBR's assumption that 'similar problems have similar solutions' enables it to understand the contexts for its experiences and the 'bigger picture' from clusters of cases, but also where its similarity assumption is challenged. Here we explore cognition and meta-cognition for CBR through self-refl ection and introspection of both memory and retrieve and reuse reasoning. Our idea is to embed and exploit cognitive functionality such as insight, intuition and curiosity within CBR to drive robust, and even explainable, intelligence that will achieve problemsolving in challenging, complex, dynamic domains

Global public perceptions of genomic data sharing: what shapes the willingness to donate DNA and health data?

Analyzing genomic data across populations is central to understanding the role of genetic factors in health and disease. Successful data sharing relies on public support, which requires attention to whether people around the world are willing to donate their data that are then subsequently shared with others for research. However, studies of such public perceptions are geographically limited and do not enable comparison. This paper presents results from a very large public survey on attitudes toward genomic data sharing. Data from 36,268 individuals across 22 countries (gathered in 15 languages) are presented. In general, publics across the world do not appear to be aware of, nor familiar with, the concepts of DNA, genetics, and genomics. Willingness to donate one's DNA and health data for research is relatively low, and trust in the process of data's being shared with multiple users (e.g., doctors, researchers, governments) is also low. Participants were most willing to donate DNA or health information for research when the recipient was specified as a medical doctor and least willing to donate when the recipient was a for-profit researcher. Those who were familiar with genetics and who were trusting of the users asking for data were more likely to be willing to donate. However, less than half of participants trusted more than one potential user of data, although this varied across countries. Genetic information was not uniformly seen as different from other forms of health information, but there was an association between seeing genetic information as special in some way compared to other health data and increased willingness to donate. The global perspective provided by our "Your DNA, Your Say" study is valuable for informing the development of international policy and practice for sharing genomic data. It highlights that the research community not only needs to be worthy of trust by the public, but also urgent steps need to be taken to authentically communicate why genomic research is necessary and how data donation, and subsequent sharing, is integral to this

Transgenic mice with chronic NGF deprivation and Alzheimer's disease-like pathology display hippocampal region-specific impairments in short- and long-term plasticities

The etiology of Alzheimer's disease (AD) remains elusive. The "amyloid" hypothesis states that toxic action of accumulated \u3b2-amyloid peptide (A\u3b2) on synaptic function causes AD cognitive decline. This hypothesis is supported by analysis of familial AD (FAD)-based transgenic mouse models, where altered amyloid precursor protein (APP) processing leads to A\u3b2 accumulation correlating with hippocampal-dependent memory deficits. Some studies report prominent dentate gyrus (DG) glutamatergic plasticity alterations in these mice, while CA1 plasticity remains relatively unaffected. The "neurotrophic unbalance" hypothesis, on the other hand, states that AD-related loss of cholinergic signaling and altered APP processing are due to alterations in nerve growth factor (NGF) trophic support. This hypothesis is supported by analysis of the AD11 mouse, which exhibits chronic NGF deprivation during adulthood and displays AD-like pathology, including A\u3b2 accumulation and hippocampal-dependent memory deficits. In this study, we analyzed CA1 and DG glutamatergic plasticity in AD11 mice to evaluate whether these mice also share with FAD models a common phenotype in hippocampal synaptic dysfunction. We report that AD11 mice display age-dependent short- and long-term DG plasticity deficits, while CA1 plasticity remains relatively spared. We also report that both structures exhibit enhanced glutamatergic transmission under lower, yet physiological, neurotransmitter release conditions, a defect that should be considered when further evaluating hippocampal synaptic deficits underlying AD pathology. We conclude that severe deficits in DG plasticity represent another common denominator between these two etiologically different types of AD mouse models, independent of the initial insult (overexpression of FAD mutation or NGF deprivation)

Transgenic mice with chronic NGF deprivation and Alzheimer's disease-like pathology display hippocampal region-specific impairments in short- and long-term plasticities

The etiology of Alzheimer's disease (AD) remains elusive. The "amyloid" hypothesis states that toxic action of accumulated beta-amyloid peptide (A beta) on synaptic function causes AD cognitive decline. This hypothesis is supported by analysis of familial AD (FAD)-based transgenic mouse models, where altered amyloid precursor protein (APP) processing leads to A beta accumulation correlating with hippocampal-dependent memory deficits. Some studies report prominent dentate gyrus (DG) glutamatergic plasticity alterations in these mice, while CA1 plasticity remains relatively unaffected. The "neurotrophic unbalance" hypothesis, on the other hand, states that AD-related loss of cholinergic signaling and altered APP processing are due to alterations in nerve growth factor (NGF) trophic support. This hypothesis is supported by analysis of the AD11 mouse, which exhibits chronic NGF deprivation during adulthood and displays AD-like pathology, including A beta accumulation and hippocampal-dependent memory deficits. In this study, we analyzed CA1 and DG glutamatergic plasticity in AD11 mice to evaluate whether these mice also share with FAD models a common phenotype in hippocampal synaptic dysfunction. We report that AD11 mice display age-dependent short-and long-term DG plasticity deficits, while CA1 plasticity remains relatively spared. We also report that both structures exhibit enhanced glutamatergic transmission under lower, yet physiological, neurotransmitter release conditions, a defect that should be considered when further evaluating hippocampal synaptic deficits underlying AD pathology. We conclude that severe deficits in DG plasticity represent another common denominator between these two etiologically different types of AD mouse models, independent of the initial insult (overexpression of FAD mutation or NGF deprivation)