A Paradigm-Changing Surprise from Dentate Gyrus Granule Cells-Cilium-Localized p75NTR May Drive Their Progenitor Cell Proliferation

Ubaldo Armato^1*, Balu Chakravarthy², Anna Chiarini¹, Ilaria Dal Pr๠and James F. Whitfield²

¹Histology & Embryology Section, Department of Life & Reproduction Sciences, University of Verona Medical School, Verona, Venetia, Italy

²Molecular Signaling Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada

Corresponding Author:

Dr. Ubaldo Armato, MD
Histology & Embryology Section
Department of Life & Reproduction Sciences
8 Strada Le Grazie, I-37134, Verona, Italy
Tel: +39-045-8027159
Fax: +39-045-8027159
E-mail: uarmato@gmail.com

Received date: October 12, 2011; Accepted date: November 15, 2011; Published date: November 17, 2011

Citation: Armato U, Chakravarthy B, Chiarini A, Prà ID, Whitfield JF (2011) A Paradigm-Changing Surprise from Dentate Gyrus Granule Cells-Cilium- Localized p75^NTR May Drive Their Progenitor Cell Proliferation. J Alzheimers Dis 1:e104. doi:10.4172/2161-0460.1000e104

Copyright: © 2011 Armato U, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abbreviations

Aβ : Amyloid β peptide; Ach: Acetylcholine; AD: Alzheimer's Disease; BDNF: Brain-Derived Neurotrophic Factor; BFCSNs: Basal Forebrain Cholinergic Septal Neurons; DGy: Dentate Gyrus; GN: Granule Neuron; LTP: Long-Term Potentiation; NGF: Nerve Growth Factor; NT-3: Neuro-Trophin-3; p75^NTR: p75 Neuro- Trophin Receptor; SGZ: Sub-Granular Zone; SST: Somatostatin; SSTR3: SST Receptor 3; SVZ: Sub-Ventricular Zone; TA Transit-Amplifying; tPA: tissue Plasminogen Activator 2

The dentate gyrus (DGy) is made up mainly of granule neurons (GNs) with interspersed GABAergic interneurons. The subgranular zone (SGZ) of the DGy is one of the two main sites of neurogenesis (the subventricular zone [SVZ] is the other) in adult mice and humans being inhabited by progenitor granular cells and their transit amplifying (TA) progeny [1,2]. The GNs and hilar neurons produce neuro-trophins, such as brain-derived neuro-trophic factor (BDNF), nerve growth factor (NGF) and neuro-trophin-3 (NT-3), which selectively activate different Trk-family receptors [3]. The signals from these receptors attract receptor-bearing axons from basal forebrain cholinergic septal neurons (BFCSNs) to extend along the septo-hippocampal pathway and terminate on dendrites of neurons residing in the DGy molecular layer [4-6]. The BFCSNs axons terminate mainly in the inner molecular layer and the hilus, but not in the GNs layer [6]. The progenitor and TA neurons in the SGZ are in synaptic contact with the cholinergic axons of the BFCSNs and they express acetylcholine (Ach) receptors, which enable them to respond to the local diffuse availability of ACh [4]. The BFCSN axons release Ach, which promotes progenitor neuron proliferation as well as the survival and maturation of TA neurons in the SGZ. Conversely, inhibiting ACh activity or selectively killing BFCSNs with the monoclonal anti-NGF 192 IgG antibody-saporin immunotoxin inhibits the SGZ production of new neurons [4,7] (Figures 1 and 2).

The signals from Trk A receptors activated by mature NGF moieties in the DGy keep BFCSNs alive and their axons producing ACh. But with age and advancing Alzheimer's disease (AD), the proteolytic conversion of pro-NGF to mature NGF by plasmin declines as the result of an amyloid β _1-42 (Aβ _1-42)- induced fall of tPA (tissue plasminogen activator) availability [3]. This causes a build-up of pro-NGF, which in turn brings about the decline of the mature NGF TrkA receptor and the rise of pro-NGF's p75^NTR receptor and of its association with the sortilin co-receptor instead of TrkA on the cholinergic BFCSN axons [3] (Figure 2). The signals from the pro-NGF-activated p75^NTR receptors kill the BFCSNs and with them suppress the "biphasic" support for hippocampal memory encoding by which high Ach levels first favor memory encoding but hinder memory consolidation and retrieval, and low ACh levels improve both memory firming and retrieval [3,8] (Figure 1 and 2).

According to the current paradigm, p75^NTR is only very sparsely expressed in the normal adult hippocampus and then only on BFCSN axons in aging and AD brains [9]. But something very important about hippocampal p75^NTR role has been hitherto missed! According to a recent report [10] at least 90% of the DGy GNs in normal adult mice between 6 to 24 months-old have a 4.0-µm-long primary cilium protruding from them, in which they confine p75^NTR along with somatostatin receptor 3 (SSTR3; Figure 3). Evidently this cilial p75^NTR does not kill normal DGy GNs. And the cilia in which p75^NTR is confined are known to be needed for adult neurogenesis [2,11].

Figure 1: The key role of p75NTR in the generation of DGy GNs. In this cheme, a neuro-trophin (BDNF or NGF) in the DGy SGZ activates cilial p75NTR, the signals from which stimulate progenitor cell proliferation and the generation of rapidly proliferating TA precursor neurons. After several rounds of proliferation, the TA precursor neurons stop proliferating and signals 6 from the cilial SSTR3 and BDNF�TrkB complexes stimulate them to mature, enter the granule cell layer and serve transiently as intensive long-term potentiation (LTP)- generating, super-sensitive encoders of novel multi-modal inputs flowing along the perforant pathway from the entorhinal cortex. Normally, half or more of the newborn cells may die without reaching the granule cell layer. But NGF produced in the DGy from proNGF by tPA-generated plasmin forms NGF�Trk A complexes that stimulate BFCSNs to make Ach and release it in the hippocampus, which promotes newborn neurons survival and thus neurogenesis and memory formation. Eventually, the successful neurons lose their hyper-responsiveness and become loaded with old �memories�, retire, and are replaced with new recorders.

Figure 2: The Aβ peptides accumulating in the early stages of AD also stimulate cilial p75NTR like the neuro-trophins and with this the proliferation of granule cell progenitors and their TA progeny. But the additional neurogenesis expected from this stimulation fails and neurogenesis drops because proNGF can no longer be converted into mature NGF because of a developing shortage of plasmin resulting from an Aβ1-42-induced fall in tPA. But proNGF preferentially binds and activates the p75NTRâÂ?¢sortilin complexes instead of NGFâÂ?¢TrkA complexes on the BFCSN axons. The retrograde flow of p75NTRâÂ?¢sortilin signals down the axons kills the BFCSNs and stops the hippocampal supply of ACh that would otherwise promote the survival of the TA precursor neurons. Furthermore, TA neurons that do survive are prevented from further maturing by the lack of SST?a hallmark of the AD brain?and the consequent silencing of SSTR3 signaling.

Figure 3: More than 90% of the murine DGy GNs have a ~4-�µm-long cilium protruding from them. These cilia are loaded with p75NTR, the signals from which can stimulate granule cell progenitor proliferation, and also with SSTR3 (not shown), the signals from which can drive the postmitotic maturation of newborn neurons.

So what might the cilially restricted p75^NTR do for adult neurogenesis? Key clues to its function are: (i) proliferating (i.e., BRDU-positive) cells in the DGy SGZ express p75^NTR; and (ii) knocking out p75^NTR reduces the proliferating cells and hippocampal neurogenesis by 59%-79% [12,13]. Although we do not yet know whether the progenitor cells in the other adult neurogenesis region, the SVZ [1], also confine p75^NTR to their primary cilia, BDNF-, NGF- or Aβ 1-42-induced p75^NTR signaling stimulates their proliferation and neurogenesis without requiring BDNF's or NGF's corresponding TrkB or TrkA co-receptors [14,15]. Therefore, cilial p75^NTR is a driver of the proliferative stage of adult neurogenesis (Figures 1 and 2).

The ability of the proliferogenic cilial p75^NTR to bind and be activated by Aβ _1-42 [14,16] (Figures 2 and 3) can explain a so far mysterious aspect of adult neurogenesis in early AD. Progenitor cell proliferation and adult neurogenesis normally decline with age, and it would be expected to at least continue dropping with the approach of AD [1,17-19]. But the ability of Aβ _1-42 to activate the proliferogenic p75^NTR reverses this trend and progenitor cell proliferation counter-intuitively increases in the early Aβ _1-42-accumulating stages of AD [17-19]. While this is happening, the pro-NGF-activated axonal p75^NTR.sortilin complexes induced by the accumulating Aβ _1-42 start killing BFCSNs and cutting off the hippocampal supply of ACh [3]. Also counter-intuitively despite the increased Aβ _1-42/p75^NTR-driven progenitor cell proliferation, neurogenesis is not increased because fewer TA neurons can survive without the support of ACh and because the cilial SSTR3 receptors needed for maturation and memory functions [20] are silenced by the lack of SST in AD brains [21] (Figure 2)

In conclusion, cilial p75^NTR must now be part of models of adult neurogenesis in the DGy and memory formation and of the cognitive decline in aging and AD brains.

References

1. Kempermann G (2011) Adult Neurogenesis 2. Oxford University Press, New York.
2. Whitfield JF, Chakravarthy BR (2009) The neuronal primary cilium: driver of neurogenesis and memory formation in the hippocampal dentate gyrus? Cell Signal 21: 1351-1355.
3. Fortress AM, Buhusi M, Helke KL, Granholm AC (2011) Cholinergic degeneration and alteration in the TrkA and p75^NTR balance as a result of pro- NGF injection into aged rats. J Aging Res 460543.
4. Bruel-Jungerman E, Lucassen PL, Francis F (2011) Cholinergic influences on cortical development and adult neurogenesis. Behav Brain Res 221: 379-388.
5. Butcher LR, Woolf NJ (2004) Cholinergic neurons and networks revisited, in: The Rat Nervous System, 3rdedn., G. Paxinos, ed. Elsevier-Academic Press, San Diego.
6. Makuch R, Baratta J, Karaelias LD, Lauterborn JC, Gall CM, et al. (2001) Arrival of afferents and the differentiation of target neurons: studies of developing cholinergic projections to the dentate gyrus. Neuroscience 104: 81-91.
7. Van der Borght K, Mulder J, Keijser JN, Eggen BJL, Luiten PGM, et al. (2005) Input from the medial septum regulates adult hippocampus neurogenesis. Brain Res Bull 67: 117-125.
8. Micheau J, Marighetto A (2011) Acetyl choline and memory: a long, complex and chaotic but still living relation. Behav Brain Res 221: 424-429.
9. Zeng F, Lu JJ, Zhou XF, Wang YJ (2011) Roles of p75NTRin the pathogenesis of Alzheimer's disease: a novel therapeutic target. Biochem Pharmacol 82: 1500-1509
10. Chakravarthy B, Gaudet C, Ménard M, Atkinson T, Chiarini A, et al. (2010) The p75 neurotrophin receptor is localized to primary cilia in adult mouse hippocampal dentate gyrus granule cells. Biochem Biophys Res Commun 401: 458-462.
11. Han YG, Spassky N, Romaguera-Ros M, Garcia-Verdugo JM, Aguilar A, et al. (2008) Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci 11: 277-284.
12. Bernabeu RO, Longo FM (2010) The p75 neurotrophin receptor is expressed by adult mouse dentate progenitor cells and regulates neuronal and nonneuronal cell genesis. BMC Neuroscience 11: 136-146.
13. Colditz MJ, Catts VS, Al-menhali N, Osborne GW, Bartlett PF, et al. (2010) p75 neurotrophin receptor regulates basal and fluoxetine-stimulated hippocampal neurogenesis. Exp Brain Res 200 :161-167.
14. Sotthibundhu A, Li QX, Thangnipon W, Coulson EJ (2009) Abeta(1-42) stimulates adult SVZ neurogenesis through the p75 neurotrophin receptor. Neurobiol Aging 30: 1975-1985.
15. Young KM, Merson TD, Sotthibundhu A, Coulson EJ, Bartlett PF (2007) p75 neurotrophin receptor expression defines a population of BDNF-responsive neurogenic precursor cells. J Neurosci 27: 5146-5155.
16. Chiarini A, Dal Prà I, Whitfield JF, Armato U (2006) The killing of neurons by beta-amyloid peptides, prions , and proinflammatory cytokines. Ital J Anat Embryol 111: 221-246.
17. Avila J, Insausti R, Del Rio J (2010) Memory and neurogenesis in aging and Alzheimer's disease. Aging Dis 1: 30-36.
18. Shetty AK (2010) Reelin signaling, hippocampal neurogenesis, and efficacy of aspirin intake & stem cell transplantation in aging and Alzheimer's disease. Aging Dis 1: 2-11.
19. Waldau R, Shetty AK (2008) Behavior of neural stem cells in the Alzheimer brain. Cell Mol Life Sci 65: 2372-2384.
20. Einstein EB, Patterson CA, Hon BJ, Regan KA, Reddi J, et al. (2010) Somatostatin signaling in neuronal cilia is critical for object recognition memory. J Neurosci 30: 4306-4314.
21. Burgos-Ramos E, Hervás-Aguilar A, Aguado-Liera D, Puebla-Jiménezal, Hernández-Pinto AM, et al. (2008) Somatostatin and Alzheimer's disease. Mol Cell Endocrinol 286: 104-111.