Adult hippocampal neurogenesis impairment at preplaque stage in a transgenic rat model of Alzheimer like amyloid pathology

The contribution of adult hippocampal neurogenesis (AHN) impairment on cognitive decline in early Alzheimer disease (AD) remains poorly understood. This can be ascribed to the technical difficulties to measure AHN in postmortem brains and patients. Furthermore, most animal models of AD exhibit an aggressive neuropathology at early age and harbor gene mutations and express transgenes that disrupts AHN by pathways not directly involved in AD pathology. To overcome some of these limitations, we studied AHN at preplaque stage (6 month old) in hemizygous (Tg+/-) and homozygous (Tg+/+) McGill-R-Thy1-APP transgenic rats. This model exhibits a much less aggressive neuropathology that nevertheless is associated with a marked cognitive impairment from early age. Our results revealed that Tg+/+ rats showed a reduced number of PCNA+ cells, DCX+ immature neurons and BrdU+/NeuN+ colabed neurons in dorsal and ventral dentate gyrus. Moreover, dendritic arborization was less developed. AHN was not impaired in Tg+/- rats, although dendritic arborization was slightly decreased. On the other hand, both hemizygous and homozygous rats exhibited spatial memory impairments in the Morris water maze. These results suggest that 1) AHN is dysregulated from the preplaque stage in homozygous rats, 2) AHN impairment is dependent on APP transgene copy numbers since hemizygous rats did not show it, 3) Dysregulation of AHN is not directly associated with spatial memory impairments since hemizygous rats exhibited spared neurogenesis despite showing spatial memory deficits. Funding: International Society for Neurochemistry CAEN Grant and Andalucia TECH-ICE (PG), and PICT-2015-0285 (LM).Fil: Galeano, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Dalmasso, María Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Prestia, Federico Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Cuello, Augusto Claudio. McGill University; CanadáFil: Santín Nuñez, Luis Javier. Universidad de Málaga; EspañaFil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaThe International Society for Neurochemistry and the American Society for Neurochemistry MeetingMontrealCanadáInternational Society for NeurochemistryAmerican Society for Neurochemistr

Chronic Hippocampal Expression of Notch Intracellular Domain Induces Vascular Thickening, Reduces Glucose Availability, and Exacerbates Spatial Memory Deficits in a Rat Model of Early Alzheimer

The specific roles of Notch in progressive adulthood neurodegenerative disorders have begun to be unraveled in recent years. A number of independent studies have shown significant increases of Notch expression in brains from patients at later stages of sporadic Alzheimer’s disease (AD). However, the impact of Notch canonical signaling activation in the pathophysiology of AD is still elusive. To further investigate this issue, 2-month-old wild-type (WT) and hemizygous McGill-R-Thy1-APP rats (Tg(+/−)) were injected in CA1 with lentiviral particles (LVP) expressing the transcriptionally active fragment of Notch, known as Notch Intracellular Domain (NICD), (LVP-NICD), or control lentivirus particles (LVP-C). The Tg(+/−) rat model captures presymptomatic aspects of the AD pathology, including intraneuronal amyloid beta (Aβ) accumulation and early cognitive deficits. Seven months after LVP administration, Morris water maze test was performed, and brains isolated for biochemical and histological analysis. Our results showed a learning impairment and a worsening of spatial memory in LVP-NICD- as compared to LVP-C-injected Tg(+/−) rats. In addition, immuno histochemistry, ELISA multiplex, Western blot, RT-qPCR, and 1H-NMR spectrometry of cerebrospinal fluid (CSF) indicated that chronic expression of NICD promoted hippocampal vessel thickening with accumulation of Aβ in brain microvasculature, alteration of blood-brain barrier (BBB) permeability, and a decrease of CSF glucose levels. These findings suggest that, in the presence of early Aβ pathology, expression of NICD may contribute to the development of microvascular abnormalities, altering glucose transport at the BBB with impact on early decline of spatial learning and memory.Fil: Galeano, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Leal, Maria Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ferrari, Carina Cintia. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Dalmasso, Maria Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Martino Adami, Pamela Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Farias, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Casabona, Juan Cruz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Puntel, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Do Carmo, Sonia. Universidad McGill; CanadáFil: Smal, Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Aran, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Pitossi, Fernando Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Cuello, Augusto Claudio. Universidad McGill; CanadáFil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

International audienc

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

Introduction: Observational multimodal neuroimaging studies indicate sex differences in Alzheimer's disease pathophysiological markers. Methods: Positron emission tomography brain amyloid load, neurodegeneration (hippocampus and basal forebrain volumes adjusted to total intracranial volume, cortical thickness, and 2-deoxy-2-[fluorine-18]fluoro-D-glucose–positron emission tomography metabolism), and brain resting-state functional connectivity were analyzed in 318 cognitively intact older adults from the INSIGHT-preAD cohort (female n = 201, male n = 117). A linear mixed-effects model was performed to investigate sex effects and sex∗apolipoprotein E genotype interaction on each marker as well as sex∗amyloid group interaction for non-amyloid markers. Results: Men compared with women showed higher anterior cingulate cortex amyloid load (P =.009), glucose hypometabolism in the precuneus (P =.027), posterior cingulate (P <.001) and inferior parietal (P =.043) cortices, and lower resting-state functional connectivity in the default mode network (P =.024). No brain volumetric markers showed differences between men and women. Sex∗apolipoprotein E genotype and sex∗amyloid status interactions were not significant. Discussion: Our findings suggest that cognitively intact older men compared with women have higher resilience to pathophysiological processes of Alzheimer's disease

Association of plasma YKL-40 with brain amyloid-β levels, memory performance, and sex in subjective memory complainers

International audienc

Effect of Alzheimer's disease risk and protective factors on cognitive trajectories in subjective memory complainers: An INSIGHT‐preAD study

International audienc