Lisi Flores Aguilar

Nerve growth factor metabolic dysfunction in Down’s syndrome brains

Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimers disease and Downs syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimers disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGFs extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Downs syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Downs syndrome and age-matched controls (age range 31-68 years). We further examined primary cultures of human foetal Downs syndrome cortex (17-21 gestational age weeks) and brains from Ts65Dn mice (12-22 months), a widely used animal model of Downs syndrome. We report a significant increase in proNGF levels in human and mouse Downs syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Downs syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Downs syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Downs syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimers disease and Downs syndrome.

Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease

Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimers disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aβ) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimers disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimers disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Aβ pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest.

Searching for new pharmacological targets for the treatment of Alzheimer's disease in Down syndrome

Abstract Individuals with Down syndrome are at increased risk of developing Alzheimers disease due to increase gene dosage resulting from chromosome 21 triplication. Although virtually all adults with Down syndrome will exhibit the major neuropathological hallmarks that define Alzheimers disease, not all of them will develop the clinical symptoms associated with this disorder (i.e. dementia). Therefore, a good understanding of the pathophysiology of Alzheimers disease in Down syndrome will be crucial for the identification of novel pharmacological targets to develop disease‐modifying therapies for the benefit of Down syndrome individuals and for Alzheimers sufferers alike. The study of biomarkers will also be essential for the development of better screening tools to identify dementia at its incipient stages. This review discusses the best‐validated pharmacological targets for the treatment of cognitive impairment and Alzheimers disease in Down syndrome. We further examine the relevance of newly discovered biological markers for earlier dementia diagnosis in this population.

AF710B, an M1/sigma-1 receptor agonist with long-lasting disease-modifying properties in a transgenic rat model of Alzheimer's disease

AF710B (aka ANAVEX 3‐71) is a novel selective allosteric M1 muscarinic and sigma‐1 receptor agonist. In 3×Tg‐AD mice, AF710B attenuates cognitive deficits and decreases Alzheimer‐like hallmarks. We now report on the long‐lasting disease‐modifying properties of AF710B in McGill‐R‐Thy1‐APP transgenic (Tg) rats.

Sex differences in functional and molecular neuroimaging biomarkers of Alzheimer's disease in cognitively normal older adults with subjective memory complaints.

Observational multimodal neuroimaging studies indicate sex differences in Alzheimers disease pathophysiological markers.