Adame Castillo, Cristina

Universitat Autònoma de Barcelona. Facultat de Biociències

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ADULT NEUROGENESIS AND ALZHEIMER’S DISEASE: WHAT CAN WE LEARN?IntroductionAdult neurogenesis under normal conditions Aims Materials and methodsConclusionCristina Adame CastilloFaculty of Biosciences, Universitat Autònoma de Barcelona, Catalonia, SpainFigure 1. William Utermohlen, a painter. He was affected withAlzheimer’s disease. Note the successive self‐portraits throughthe evolution of disease [1]Figure 7. Formation of granule cells in the adult dentate gyrus [7]Figure 10. Neuronal connections in the adult dentate gyrus [2]This disease is spread in worldwide and the all casesof dementia, AD represents 70%.The molecular mechanism of AD is explained byamyloid cascade hypothesis, which is the mostinfluential model of pathology (Figure 2). This theoryproposes that in AD patients takes placeamyloidogenic pathway whereas the non‐AD patientscarry out non‐amyloidogenic pathway.The amyloid precursor peptide (APP) is atransmembranal protein. APP can be processed bythree enzymes: α‐, β‐ and γ‐secretase. If APP isprocessed by α‐secretase, the precursor will generatea soluble molecule named sAPPα and takes placesnon‐amyloidogenic pathway. Nevertheless, thecleavage due to β‐ and γ‐secretase leads toamyloidogenic pathway. The β‐secretase splits APPand it’s formed a soluble molecule sAPPβ; and theperformance of γ‐secretase releases fragments of β‐amyloid peptides (Aβ), a toxic specie.The senile plaques are formed by the accumulationof Aβ in extracellular space. These deposit can beinternalised by cells leading to cell death.Figure 2. The APP processing [2]1. To study how neurogenesis takes place in adult brains.2. To understand how Alzheimer’s disease alters adult neurogenesis in 3xTg‐AD mice, a murine model ofthis neurodegenerative entity.3. To extrapolate the affectations in 3xTg‐AD mouse model to humans patients affected with Alzheimer’sdisease.Embryonic radial glia gives rise type B cells (astrocyte)which have the capacity of self‐renewing and originatetype C cells (transit progenitor); see Figure 5. Thesecells give rise neuroblasts (type A cells) which migrateto olfactory bulb through rostral migratory stream(Figure 6).Subventricular zone________________________Subgranular zone_______________________________________Type 1 cells give rise amounts of type 2 cells, a neural precursor cell(NPC), according to specific markers expression (see Figure 8 and 9).While the neural precursor cells are differentiating, these are moving withindentate gyrus radial or transversally. These precursor give rise neuroblasts whichmigrate along dentate gyrus generating glutamatergic granule cells. These granulecells make grow up axons to CA‐3 and ramifying dendrites to molecular layer ofdentate gyrus.The information flows from glutamatergic granule cells to CA‐3; the CA‐3 neuron’sreceives the information and it’s send to CA‐1. From this field, the information issent to deep layers of enthorinal cortex. Finally, the information come back toglutamatergic granule cells of dentate gyrus (Figure 10).The new cells, which arrive at olfactory bulb, can bemature or young neurons. These cells migrate to catchup the granular or periglomerular layer to integrate inneural network.Figure 6. The new neurons migrate from lateral ventricle (SVZ)to olfactory bulb (OB) through rostral migratory stream (RMS).Subgranular zone of dentate gyrus (SGZ) is also indicated [6].3xTg‐AD mouse model harbourshuman mutations:• APPswe• PS1M146V• TauP301L3xTg‐AD females show amyloid and tau‐pathologies homologous to humans. Micepresent severe depletion of neurons inseveral areas of the CNS including cerebralcortex, amygdala and hippocampus.Alzheimer’s disease (AD) is a neurodegenerativeillness and is the most common form of dementia.This pathology causes behavioural issues,disorientation, mood swings and cognition worsening.Some of them had been recreated in artwork (seeFigure 1).The neurofibrillary tangles are made ofhyperphosphorylated tau protein. Theseaccumulations in intracellular medium produces theincapacity to establish microtubules and it causesneurodegeneration.This neurological entity is characterized by reduction ofcortex volume and the presence of senile plaques (Figure3A) and neurofibrillary tangles (Figure 3B). The peoplewho suffer this illness shows impairments in memorybecause the first filed affected is the hippocampus.NeuroblastsStem cells Transit amplifying cells Figure 5. Cellular components in an adultneurogenic niche from a lateral ventricleLV indicates lateral ventricle [5]Figure 3. A and B show, respectively, a senile plaque and a neurofibrillarytangle from a patient affected with Alzheimer’s disease [3]References1. Modified from http://kissfm.emisorasunidas.com/content/autorretrato‐del‐alzheimer2. Mu Y. and Gage H., “Adult hippocampal neurogenesis and its role in Alzheimer’s disease”,Molecular Neurodegenaration (2011); 6 (85): 1‐93. From http://imgarcade.com4. From www.pixshark.com5. Alvarez and Garcia, “Neurogenesis in adult subventricular zone”, The Journal of Neuroscience (2002); 22 (3): 629‐6346. Modified from http://brainstars.org7. Aimone J.B. et al, “Regulation and function of adult neurogenesis: from genes to cognition”, Physiology Review (2014); 94: 991‐10268. Cabezas C. et al., “Molecular and functional characterization of G4D67‐expressing, newborn granule cells in mouse dentate gyrus”, Frontiers inNeural Circuits (2013); 7 (60): 1‐169. Cayre M. et al., “Cell migration in the normal and pathological postnatal mammalian brain”, Progress in Neurobiology (2009); 88(1): 41‐6310. Martinez‐Canabal A., “Reconsidering hippocampal neurogenesis in Alzheimer’s disease”, Frontiers in Neuroscience (2014); 8 (147):1‐311. From http://articles.latimes.com/2006/nov/20/health/he‐myturn20The disease’s study in triple transgenic mouse model allows to extrapolate the results to humans (Figure12):1. AD patients contain equal cytoarchitecture and the same number of cells in dentate gyrus incomparison with healthy people.2. This neurodegenerative entity affects neural stem cells and its progeny in subgranular zone of dentategyrus.3. The regeneration is disturbed by the disease leading to an imbalance impossible to restore.Figure 4. 3xTg‐AD mice model [4]Figure 9.Markersof neuralstem cellsand itsprogeny[9]Figure 8. Fluorescent image of adult dentate gyrus with specific markers. Red = NeuN (figure A), blue =Doublecortin (DCX) (figure B), merge of GFAP, NeuN and DCX (figure C) [8]A BIn the adult mammalian CNS, there are two know“neurogenic niche”: the subventricular zone (SVZ) oflateral ventricle and the subgranular zone (SGZ) of thedentate gyrus.During early development of the dentate gyrus, granule cells areoriginate from cellular precursors located in the neuroepithelium.Some of them persist in the adult dentate gyrus and establish asecondary neurogenic region: the subgranular zone. This is composedby type 1 cells, which are neural stem cells localised on spanning ofgranule cell layer and ramifying in inner molecular layer of dentategyrus (Figure 7).A B CFigure 12. Rita Hayworth, an actress who died by Alzheimer’s disease [11]ResultsLiterature data from female 3xTg‐AD indicates: Before the symptoms of Alzheimer's disease appears, the generation,migration and settling of granular neurons in dentate gyrus occurs in anormal manner because cytoarchitectonics are normal at early ages(Figure 11A). Moreover, the production of new neurons in dentate gyrusand the number of cells are conserved. In mature 3xTg‐AD mice, there is affectation in stem cells and its progeny,and granular cells in dentate gyrus. The depletion of these cellularpopulations is progressive with age of mice, and the senile plaques andneurofibrillary tangles reduce neurogenesis in this neurogenic niche(Figure 11B). Regeneration is disturbed in 3xTg‐AD due to the massive loss of stem cellsand its progeny leading to an imbalance impossible to restore. I proposethat a similar scenario occurs in patients affected with Alzheimer’s disease(Figure 11C).A. Normal mouse and healthy people B. Cellular vulnerability in 3xTg‐AD C. Presumable affectationin human Alzheimer’s diseaseFigure 11. Mature dentate gyrus showing several cellular populations. Progenitor cells divide leading to the production of new progenitors (1)and neuroblasts (2). Neuroblasts become young neurons (3) that migrate and extend neurites (A). In 3xTg‐AD, amyloid plaques are found in thegranule cell and molecular layer as well as in the subgranular zone. Stem cells and its progeny are also affected (B). A similar scenario mightoccur in the Alzheimer’s disease (C). Insets in figures A to C show cells tagged with Nestin (red), Doublecortin (yellow) and NeuN (green). Notethat less labelled cells are present in B and C versus A [10]

Adult neurogenesis and alzheimer's disease : what can we learn?

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Adult neurogenesis and alzheimer's disease : what can we learn?

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