Alzheimer's disease: An update of the roles of receptors, astrocytes and primary cilia (Review)

  • Authors:
    • Ubaldo Armato
    • Balu Chakravarthy
    • Raffaella Pacchiana
    • James F. Whitfield
  • View Affiliations

  • Published online on: October 24, 2012
  • Pages: 3-10
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


The pathophysiological mechanisms underlying the onset and inexorable progression of the late‑onset form of Alzheimer's disease (AD) are still the object of controversy. This review takes stock of some most recent advancements of this field concerning the complex roles played by the amyloid‑β (Aβ)‑binding p75 neurotrophin receptor (p75NTR) and calcium‑sensing receptor (CaSR) and by the primary cilia in AD. Apart from their physiological roles, p75NTR is more intensely expressed in the hippocampus of human AD brains and Aβ‑bound p75NTR triggers cell death, whereas Aβ‑bound CaSR signalling induces the de novo synthesis and release of nitric oxide (NO), vascular endothelial growth factor (VEGF)‑A and Aβ peptides (Aβs), particularly on the part of normal adult human astrocytes. The latter effect could significantly increase the pool of Aβ‑ and NO‑producing nerve cells favouring the progressive spread of a self‑sustaining and self‑reinforcing ‘infectious’ mechanism of neural and vascular (i.e. blood-brain barrier) cell damage. Interestingly, primary cilia concentrate p75NTR receptors in their membranes and are abnormally structured/damaged in transgenic (Tg) AD‑model mice, which could impact on the adult neurogenesis occurring in the dentate gyrus's subgranular zone (SGZ) that is necessary for new memory encoding, thereby favouring typical AD cognitive decline. Altogether, these findings may pave the way to novel therapeutic approaches to AD, particularly in its mild cognitive impairment (MCI) and pre‑MCI stages of development.

1. Introduction

Almost 2% of the people of Western industrialized countries are affected by Alzheimer’s disease (AD) (1,2). But what is this ailment that threatens a growing number people in our aging populations? It is a very slowly expanding neurodegenerative process that betrays its presence by disconnecting and ultimately destroying neural networks in the hippocampus, the brain’s ancient memory-recording and accessing ‘machine’ (3,4). The by far most common late onset AD (LOAD) cases account for over 70% of dementia cases in individuals >70 years of age (5). The incidence of AD increases exponentially with age and doubles every 5 years after the age of 65 (1). In the rare early-onset familiar AD (EOFAD) cases genetic mutations support an Aβ peptide overproduction (1,2). The LOAD pathogenesis is still controversial; it begins 30–40 years before the phenotypic emergence of clinical symptoms, in the entorhinal cortex and the dentate gyrus, where the aggregation-prone Aβ1–42 peptides (Aβs), which derive from the sequential activity of two proteases, BACE1 and γ-secretase, on the amyloid precursor protein (APP), progressively disrupt the neuronal networks (38).

In normal brains, neurons release at synapses nontoxic Aβ42 monomers, the physiological levels of which are kept at low, safe levels by various clearance mechanisms involving the activation of proteases, phagocytosis by microglia and dumping into the blood by transporters such as LRP1 (4). But in the aging brains of susceptible persons the Aβ42 clearing mechanisms start to fail and the accumulating Aβ42 monomers will aggregate into toxic soluble oligomers and protofibrils driving the brain into the onset of the pathology (3,4). Thus, AD starts stealthily maybe as early as during childhood in a subcortical region such as the locus coeruleus, from which a prion-like tau mutant would progressively spread and/or maybe in the brain’s default mode network (DMN), which includes the medial temporal memory-recording region (3,410). Aβs overproduction associates with the dangerous spread of phosphorylated tau protein (3,4,6). Ultimately, the functionally disturbed neurons cause a lethal accrual of the toxic prion-like pE Aβ3–34 (pyroglutamyl Aβ3–34) along with the Aβs oligomers with which it associates (1115). Indeed pE Aβ3–34 is likely ‘the AD’s hatchet man’ as it has been called by Jawhar et al (12).

In the present study we aim at updating some of the mechanisms supporting AD development and progression, i.e. i) the interactions of two nerve cell membrane receptors with Aβs and their effects; ii) the complex involvement of a perhaps unduly overlooked class of glial cells, the astrocytes, in AD; and iii) the involvement of the primary cilia of neurons and astrocytes alike in AD. Here we shall briefly review such topics in their own contexts.

2. Nerve cell membrane receptors in AD

p75 neurotrophin receptor (p75NTR)

The p75NTR is a TNF-family low-affinity receptor for neurotrophins such as nerve growth factor (NGF), neurotrophin (NT)-3, NT-4 and brain-derived neurotrophic factor (BDNF). The interest in p75NTR role, if any, in AD development and progression was triggered by the studies of Yaar et al (16,17) and Kuner et al (18), who showed that Aβs could bind to both p75NTR monomers and trimers, thereby activating its intracellular signalling and inducing apoptosis in human neuroblastoma cells. At about such early times, we employed neuroblastoma cell clones that did not express any of the neurotrophin receptors or had been engineered to express full-length or various truncated forms of the p75NTR to demonstrate that p75NTR binds Aβs via its extracellular domain and, as a consequence, via its death domain directly signals cell death. In fact, this signaling led to caspase-8 and caspase-3 activation and to reactive oxygen species (ROS) production and cellular oxidative stress (19,20). Moreover, the direct and indirect (inflammatory) mechanisms of neuronal damage by Aβs could interact synergistically, since cytokines released from an activated microglia, like TNF-α and IL-1β, remarkably potentiated the neurotoxic actions of the Aβs/p75NTR signaling (19,20). Altogether, these findings indicated that the privileged targets of the cytotoxic actions of Aβs in AD might be p75NTR-expressing neurons endowed with receptors for proinflammatory cytokines (19,20).

Concurrently, by means of the same human neuroblastoma cell clones either devoid of all the neurotrophin receptors or expressing the full-length or variously truncated forms of p75NTR, we could prove that the neuronal death induced by the prion protein fragment PrP106–126 is mediated through its binding to the extracellular domain of p75NTR and the subsequent signaling of its death domain causing the downstream activation of caspase-8 and production of ROS (20,21). Since then other laboratories have corroborated the idea that the Aβs/p75NTR binding engenders a signaling causing neuronal apoptosis (22,23).

More recently, we demonstrated that, besides binding and activating p75NTR receptors, Aβ1–42 and its surrogate active peptide Aβ25–35, but not the reverse sequence Aβ42-1 peptide, at least double the membrane complement of p75NTR receptors in SH-SY5Y human neuroblastoma cells (24). We concurrently established that p75NTR is overexpressed above the level of corresponding wild-type mice in the hippocampal membranes of two strains of AD transgenic mice, i) in 12–15-month-old AD-triple transgenic (Tg) mice (3xTg-AD) harboring PS1 (M146V), AβPP (Swe) and tau (P301L) and ii) in 7-month-old B6.Cg Tg-AD mice harboring PSEN1dE9 and AβPP (Swe). Importantly, this increase correlated with the age-dependent rise in Aβ1–42 levels in the AD mice (24). Evidence was also gained that the Aβ42 oligomers known as Aβ-derived diffusible ligands (ADDLs) induced the expression of p75NTR protein via the phosphorylation of insulin-like growth factor-1 receptor (IGF-1R) in SH-SY5Y human neuroblastoma cells (25). An in vivo microinjection of ADDLs also increased the p75NTR protein expression by 1.4-fold in the ipsilateral hippocampus as compared to the non-injected contralateral hippocampus. Moreover, in the ADDLs-microinjected mouse hippocampi IGF-1R phosphorylation surged within 30 min, while the co-administration of picropodophyllin, an IGF-1R kinase inhibitor, prevented any ADDLs-induced p75NTR expression from occurring (25). In addition, in the hippocampi of 6-month-old AβPPswe/PS1dE9 Tg-AD model mice that had accumulated significant amounts of Aβ1–42 a higher p75NTR protein expression together with higher levels of IGF-1R phosphorylation were detected with respect to the hippocampi from age-matched wild-type mice (25). Hence, Aβ42 oligomer-mediated IGF-1R activation may trigger an increase in p75NTR protein expression in the hippocampus of a Tg-AD mouse model brain during the early stages of disease development.

Notably, these findings raised an important question, i.e. whether the Aβ42’s accumulation is also coupled with an increased hippocampal membrane-associated p75NTR expression in human AD brains. Indeed, the mechanisms controlling the hippocampal expression of p75NTR are poorly known. It is a commonly held view that the p75NTR proteins are not expressed by the hippocampal nerve cells, but are carried to the hippocampus via the afferent axons of basal forebrain cholinergic neurons (BFCNs). Yet, BFCNs are selectively killed in the early phases of AD, which would entail a p75NTR fall in the hippocampi of AD brains (26). On the other hand, a high concentration of p75NTR receptors is detectable in the membranes of the primary cilia of dentate gyrus granule cells in the mouse hippocampus (27). Others have reported p75NTR protein expression in normal mice granule cell precursors up to the early postmitotic maturation of neuroblasts (28) and in dendritic spines and afferent terminals of hippocampal CA1 pyramidal neurons of normal C57BL/6 mice (29). To solve this question, we used polyclonal and monoclonal antibodies against the p75NTR receptor’s intra- and extracellular domains. Thus, we were able to show that the mean level of membrane-associated p75NTR in the hippocampal formation is significantly higher (~2-fold, p<0.03) in human AD brains than in identical samples of hippocampal formation in age-matched non-AD human brains (30). As yet, we do not know whether the same types of nerve cells express p75NTR receptors in murine and human hippocampi, respectively. Nevertheless, an elevated membrane-bound p75NTR in the human hippocampus could be another characteristic of AD. It remains to be determined whether and/or how such an increased expression of membrane-bound p75NTR might be a cause of the hippocampal destruction causing the cognitive decay in AD patients.

Calcium-Sensing Receptor (CaSR)

The highly conserved CaSR gene encodes the CaSR protein, which belongs to family C of G-protein-coupled receptors (GPCRs), whose members have no sequence homology with those of other GPCR families (31). The CaSR’s huge (>600 amino acids) bilobed extracellular N-terminus domain looks like a Venus Flytrap (VFT), whose lobes are joined via a three-strand hinge to 7 transmembrane α-helices (TM1–TM7) ending with the intracellular C-terminus (32). A cysteine-rich region (CRR) links the VFT to the 7TM region and is important for signal transmission from the VFT-like domain to the TM1–TM7 (33). CaSR’s intracellular tail includes two regions essential for its cell surface expression and biological activity (34). By rearranging the two 7TM regions, ligand binding permits the intracellular CaSRs C-tails to bind various G proteins (G, G and G11α) (35). CaSRs form homodimers (CaSR/CaSR) or heterodimers (CaSR/mGluR) in their membrane-bound form, although they can function even as monomers (32). Dimers are assembled at the ER to allow CaSR transport to the plasmalemma (36). The huge VFT lobes of CaSR homodimers cooperatively bind ligands, e.g. Ca2+ (35). The CaSR detects changes in [Ca2+]e (35), but is a non-selective receptor (37). Ca2+, di- and tri-valent cations, antibiotics and polyamines are the CasR-activating orthosteric agonists, whereas endogenous ligands or factors, like pH, ionic strength, [Na+]e and aromatic L-α-amino acids are the allosteric CaSR modulators (37). Intracellular signaling, mediated via Ca2+ influx, has been connected to MAPK (MEK/ERK and JNK) activation, ion channel function, gene expression, cell proliferation and cell death (35). Most significantly, even Aβs do bind and activate the CaSR (38). Hence, CaSR-expressing neurons and glial cells of all types are susceptible to the cytotoxic effects of the CasR-activating Aβ42 oligomers and fibrillar aggregates (39). The interest in CaSR’s role in AD pathogenesis has been increasing since the first evidence was gained of Aβ42/CaSR interactions in hippocampal pyramidal neurons (40). But CaSR expression by the astrocytes entails deep neuropathologic implications since they play significant roles in inflammatory and degenerative brain diseases (3941). Using cultured phenotypically stable normal adult human astrocytes freshly isolated from the temporal lobe cerebral cortex we could show that exogenous Aβ-stimulated CaSR signaling triggers i) the expression of nitric oxide synthase-2 (NOS-2); ii) the expression and activity of GTP cyclohydrolase 1 (GCH1), which produces tetrahydrobiopterin (BH4); and iii) the synthesis and release of large amounts of NO on the part of the BH4-dimerized/activated NOS-2 (4144). In its turn, the overproduced NO can be fairly damaging to neurons and glial cells (see also below).

Moreover, using the same cultured phenotypically locked-in normal adult human astrocytes exposed to normoxic conditions we could demonstrate that the Aβs/CaSR interaction also induces within 18–24 hours the nuclear translocation of the hypoxia-inducible HIF1α/HIF1β transcription complex that drives the expression of three VEGF-A splice variants (VEGF-A121, VEGF-A165 and VEGF-A189) and the increased synthesis and secretion especially of VEGF-A165 (45 and unpublished results).

Finally, and perhaps most interesting of all, the Aβ-activated CaSR signalling also stimulates the normal human adult astrocytes in culture to make significant amounts of their own Aβ42 oligomers (46), which accumulate inside the cells but are also released into the medium (our unpublished results). Thus the Aβ/CaSR-evoked signalling can simultaneously modulate the expression/production of NO, VEGF-A and Aβ42 in human astrocytes.

3. Astrocytes in AD

Neurons have attracted the most attention from people trying to understand AD pathophysiologic mechanisms (3,4). Obviously they are very important in the AD story and with them die the person’s cognition and ultimately other functions. Concerning glial cells, undeniably there are more astrocytes than neurons in the human brain, although there are arguments about the size of this majority that ranges from 1.4- to 10-fold the actual neurons’ numbers (47). Until recently, astrocytes have been relegated to simple janitorial roles: they have not been believed to be able to make Aβs, but only to sweep them up and then die if and when they accumulate too much of Aβs (48), as Aβs are supposedly only made and released by the neurons. There is an increasing realization that astrocytes are much more important than previously thought; they actually protect neurons and are in fact the neuron partners in synaptic formation and function. They physically cradle or embrace neurons (Fig. 1) (49), shielding them from the signaling noise of neighboring neurons. They keep their neuron synapses optimally functional by regulating synaptic K+, by sweeping up secreted neurotransmitters (e.g., glutamate) from the synaptic space and removing transmitters spilled into the nearby space by neighbouring neurons. Astrocytes also collaborate in neuronal signaling with their own gliotransmitters, and they can stimulate synapse formation (4750).

Recent findings have added a novel facet to this picture (Fig. 2). Astrocytes are no longer just by-standing synapse blankets that only clean up the Aβs released from shattered neurons in, for example, the increasingly cognitively disabled AD brains. Astrocytes are actually stimulated by their neuron Aβs to make and secrete their own Aβs (46 and unpublished results). This means that as astrocyte-contacting neurons in key regions of the brain enter the covert early stages of AD and start over-secreting Aβs, they directly spray the astrocytes with their Aβs. The exciting finding is that this causes the same astrocytes to make and release their own Aβs and spread them to other neurons in local networks, stimulating such neurons to join and enlarge the pool of cells making Aβs. In this way, Aβs-exposed astrocytes act as vectors of a contagious, self-sustaining and Aβs-spreading disease. But this might not last, as the accumulating Aβs released from both neurons and astrocytes reach a level that stimulates the latter cells to start making large amounts of nitric oxide (NO), from which highly toxic peroxynitrites (ONOO-) can be engendered (4144). Both these diffusible agents damage neurons and astrocytes to the point of inducing cell death. Obviously, the progressive loss of astrocytes besides neurons impairs synaptic function and the provision of supplies from the circulation (47,49,51).

Amongst other activities, astrocytes send information about the activities of the neurons they cradle to their end-feet on local blood vessels, which adjusts the blood flow to provide the glucose and oxygen needed to feed the busy neurons. However, as in vitro (45), the accumulating Aβs in the key regions of the pre-AD brain such as the dentate gyrus and the CA3 subregions also stimulate astrocytes to make VEGF-A (5254), which as expected stimulates the growth of blood vessels (Fig. 3). This increase in the local vascular density magnifies the blood flow and the blood oxygen-dependent (BOLD) functional magnetic resonance imaging (fMRI) signaling from an active region such as a hippocampus trying to respond to a dentate gyrus/CA3-directed task (55,56). This has been wrongly interpreted as if the already declining hippocampi of AD-bound people with pre-AD mild cognitive impairment (MCI) are hyperactive, which they are not (5759). Again, in the early stages the VEGF-expanded vascular networks are intact and the blood vessels are functional, but this ends when the accumulating Aβs stimulate the astrocytes (and microglia) to make huge, damaging amounts of NO, which contributes to the perforation and severing of the blood vessels and with this the breaching of the blood-brain barrier and its disastrous consequences for brain function (60,61) (Fig. 3).

4. Nerve cell primary cilia in AD

Contrary to the old neurological tenet, in the brain of adult humans and rodents there are two principal areas in which neurogenesis does occur, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) (6264). In the hippocampal SGZ a pool of neural stem cells, the astrocyte-like type 1 radial glial cells, are able to produce new granule cells when they are needed for memory encoding (65,66). These cells express some properties of the astrocytes, including glial fibrillary acidic protein (GFAP), the typical astrocytic marker, are endowed with vascular end-feet and occupy their special SGZ niche: the upshot is a blood vessel-associated gap-junctionally interconnected astrocytic syncytium. Most of these cells possess non-motile, 4–8 μm-long sensory antennas protruding from their bodies, the primary cilia, wrapped in a plasma membrane that is stuffed with various kinds of receptors. Among the receptors found in the rodent granule cell cilia are the p75NTR receptor (10,24,39), the somatostatin type 3 receptor (SSTR3) (67,68) and the Sonic hedgehog (Shh) system’s smoothened (SMO) and Patched (Ptch) proteins (65,6972). Conversely, the neurotrophin tyrosine kinase receptor TrkA does not co-localize in the primary cilia membrane. Signals from the receptors on these cilia are believed to drive several fundamental activities such as neurogenesis, neuroblast maturation and memory encoding. Neurotrophin (e.g., BDNF)-induced p75NTR signalling from the primary cilia drives the proliferation of granule cells precursors in the SVZ of the dentate gyrus, as preventing this signalling severely reduces neurogenesis (65,66,73).

How these primary cilia might be involved in AD-linked cognitive deterioration? It appears that the accumulating toxic Aβ42 oligomers in AD brains at first stimulate the proliferation of GC progenitors. But later, when such oligomers are caught in the fibrillary plaques, the newly formed neuroblasts cannot mature or ultimately survive (7476). The failure of the newly generated neurons to mature and the resulting granule cell layer shrinkage and memory failure is likely, at least partly, to be due to the characteristic decline of somatostatin in AD and with it of the cilial SSTR3 signalling needed for memory encoding (65,66). These notions enticed us to surmise that primary cilium damage may cause the crippling decline of new memory formation in AD (77). This view is supported by the striking shortening of dentate gyrus granule cell primary cilia linked to the strongly reduced neurogenesis in AD Tg mice accumulating both Aβ42 and tau protein (78,79).

Moreover, cilial p75NTR can be bound and activated by Aβ42 (19,22). This would elicit an initially increased neural progenitor cell proliferation in the early stages of AD (8082), meanwhile, the hippocampal supply of acetylcholine (Ach) is progressively reduced by the accumulating Aβ42 that kills Ach-producing basal forebrain cholinergic septal neurons (BFCSNs) (83). Thus, despite the increased Aβ42/p75NTR-stimulated progenitor cell proliferation, neurogenesis is not actually increased because fewer progenitor cells survive in the lack of Ach and cilial SSTR3 receptor signalling essential for neuroblasts maturation and de novo memory encoding (65) is silenced by the absence of SST in AD brains (66,84).

In this context, a mention is deserved by the Leptin-induced signalling from Leptin b-receptors located in the cell (not primary cilium) membrane, which may also stimulate, via the Shh Smo and the release of cilium-located Gli-A nuclear transcription factor, the primary cilium-dependent proliferation of transit-amplifying progenitors in the dentate gyrus of the adult hippocampal formation (85). It follows that daily doses of Leptin might halt AD development if given perhaps in the pre-MCI or MCI stage of the ailment (86).

However, some caution is at present warranted. These tiny primary cilia are a technical challenge to isolate and directly analyse. In addition, we presently do not know whether human dentate gyral granule cells are ciliated or whether human neuroblast maturation and integration into the granule cell layer of SVZ are also driven from primary cilia. On an encouraging note, we have indeed found ciliated cells in samples of hippocampi from octogenarian normal and AD humans and in phenotypically normal astrocytes isolated from adult human cerebral cortices (82).

5. Conclusions

It is quite clear from the foregoing discussion that AD will not be understood by only considering neurons (3,4) and microglia (87). We must take into account the intimate collaboration between neurons and their astrocyte cradlers and trans-network communications. In other words we must pay serious attention to the astrocytes’ roles in AD. Moreover, at the subcellular level, important protagonists are emerging such as primary cilia and receptors such as the p75NTR and the CaSR (88), as their interactions with Aβs can modulate or alter fundamental cellular functions like Aβ42, NO, VEGF-A and proinflammatory cytokine production and release, proliferative responses and/or damage and malfunctioning of cerebral blood vessels, neurogenesis and cell death. Although as for now the AD picture seems to be more intricate than ever, we hope that these and other new acquisitions on the pathophysiologic mechanisms of this ailment will help pave the way to novel, hopefully effective therapeutic approaches.


The authors are deeply indebted to Drs I. Dal Prà, A. Chiarini, C. Gaudet, M. Ménard, T. Atkinson and L. Brown whose dedicated and intense collaboration was indispensable to achieve many of the scientific results mentioned in this study.



Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimers Dement. 4:110–133. 2008.


Kukull WA, Higdon R, Bowen JD, McCormick WC, Teri L, Schellenberg GD, van Belle G, Jolley L and Larson EB: Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol. 59:1737–1746. 2002. View Article : Google Scholar : PubMed/NCBI


Querfurth HW and LaFerla FM: Alzheimer’s disease. N Engl J Med. 362:329–344. 2010.


Selkoe DJ, Mandelkow E and Holtzman DM: The Biology of Alzheimer Disease. Cold Spring Harbor Laboratory Press; Cold Spring Harbor, NY: 2012


Choy RW, Cheng Z and Schekman R: Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid β (Aβ) production in the trans-Golgi network. Proc Natl Acad Sci USA. 109:E2077–E2082. 2012.PubMed/NCBI


LaFerla FM, Green KN and Oddo S: Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci. 8:499–509. 2007.


Li S, Shankar GM and Selkoe DJ: How do soluble oligomers of amyloid beta-protein impair hippocampal synaptic plasticity? Front Cell Neurosci. 4:52010.PubMed/NCBI


Siegenthaler BM and Rajendran L: Retromers in Alzheimer’s disease. Neurodegener Dis. 10:116–121. 2012.


Whitfield JF: The road to LOAD (late-onset Alzheimer’s disease) and possible ways to block it. Expert Opin Ther Targets. 11:1257–1260. 2007.


Dal Prà I, Chiarini A, Pacchiana R, Chakravarthy B, Whitfield JF and Armato U: Emerging concepts of how β-amyloid proteins and pro-inflammatory cytokines might collaborate to produce an ‘Alzheimer brain’ (Review). Mol Med Rep. 1:173–178. 2008.


Hartlage-Rübsamen M, Morawski M, Waniek A, Jäger C, Zeitschel U, Koch B, Cynis H, Schilling S, Schliebs R, Demuth HU and Rossner S: Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms. Acta Neuropathol. 121:705–719. 2011.PubMed/NCBI


Jawhar S, Wirth O and Bayer TA: Pyroglutamate amyloid-β (Aβ): a hatchet man in Alzheimer disease. J Biol Chem. 286:38825–38832. 2011.


Nussbaum JM, Schilling S, Cynis H, Silva A, Swanson E, Wangsanut T, Tayler K, Wiltgen B, Hatami A, Rönicke R, Reymann K, Hutter-Paier B, Alexandru A, Jagla W, Graubner S, Glabe CG, Demuth HU and Bloom GS: Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β. Nature. 485:651–655. 2012.PubMed/NCBI


Prusiner SB: Cell biology. A unifying role for prions in neurodegenerative diseases. Science. 336:1511–1513. 2012. View Article : Google Scholar : PubMed/NCBI


Stöhr J, Watts JC, Mensinger ZL, Oehler A, Grillo SK, DeArmond SJ, Prusiner SB and Giles K: Purified and synthetic Alzheimer’s amyloid beta (Aβ) prions. Proc Natl Acad Sci USA. 109:11025–11030. 2012.


Yaar M, Zhai S, Pilch PF, Doyle SM, Eisenhauer PB, Fine RE and Gilchrest BA: Binding of β-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer’s disease. J Clin Invest. 100:2333–2340. 1997.


Yaar M, Zhai S, Fine RE, Eisenhauer PB, Arbie BL, Stewart KB and Gilchrest BA: Amyloid-β binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling. J Biol Chem. 277:7720–7725. 2001.


Kuner P, Schubenel R and Hertel C: β-amyloid binds to p75NTR and activates NF-kappaB in human neuroblastoma cells. J Neurosci Res. 54:798–804. 1998.


Perini G, Della-Bianca V, Politi V, Della Valle G, Dal Prà I, Rossi F and Armato U: Role of p75 neurotrophin receptor in the neurotoxicity by β-amyloid peptides and synergistic effect of inflammatory cytokines. J Exp Med. 195:907–918. 2002.


Chiarini A, Dal Prà I, Whitfield JF and Armato U: The killing of neurons by beta-amyloid peptides, prions and pro-inflammatory cytokines. Ital J Anat Embryol. 111:221–246. 2006.PubMed/NCBI


Della-Bianca V, Rossi F, Armato U, Dal Prà I, Costantini C, Perini G, Politi V and Della Valle G: Neurotrophin p75 receptor is involved in neuronal damage by prion peptide-(106-126). J Biol Chem. 276:38929–38933. 2001. View Article : Google Scholar : PubMed/NCBI


Sotthibundhu A, Li QX, Thangnipon W and Coulson EJ: Abeta(1–42) stimulates adult SVZ neurogenesis through the p75 neurotrophin receptor. Neurobiol Aging. 30:1975–1985. 2009.


Bai M, Trivedi S and Brown EM: Dimerization of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaR-transfected HEK293 cells. J Biol Chem. 273:23605–23610. 1998. View Article : Google Scholar : PubMed/NCBI


Chakravarthy B, Gaudet C, Ménard M, Atkinson T, Brown L, Laferla FM, Armato U and Whitfield J: Amyloid-beta peptides stimulate the expression of the p75(NTR) neurotrophin receptor in SHSY5Y human neuroblastoma cells and AD transgenic mice. J Alzheimers Dis. 19:915–925. 2010.PubMed/NCBI


Ito S, Ménard M, Atkinson T, Gaudet C, Brown L, Whitfield J and Chakravarthy B: Involvement of insulin-like growth factor 1 receptor signaling in the amyloid-β peptide oligomers-induced p75 neurotrophin receptor protein expression in mouse hippocampus. J Alzheimers Dis. 31:493–506. 2012.


Mufson EJ, Ma SY, Dills J, Cochran EJ, Leurgans S, Wuu J, Bennett DA, Jaffar S, Gilmor ML, Levey AI and Kordower JH: Loss of basal forebrain P75 (NTR) immunoreactivity in subjects with mild cognitive impairment and Alzheimer’s disease. J Comp Neurol. 443:136–153. 2002.PubMed/NCBI


Chakravarthy B, Gaudet C, Ménard M, Atkinson T, Chiarini A, Dal Prà I and Whitfield J: The p75 neurotrophin receptor is localized to primary cilia in adult mouse hippocampal dentate gyrus granule cells. Biochem Biophys Res Commun. 401:458–462. 2010. View Article : Google Scholar : PubMed/NCBI


Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, Hempstead BL and Lu B: Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci. 8:1069–1077. 2005. View Article : Google Scholar : PubMed/NCBI


Bernabeu RO and Longo FM: The p75 neurotrophin receptor is expressed by adult mouse dentate progenitor cells and regulates neuronal and non-neuronal cell genesis. BMC Neurosci. 11:1362010. View Article : Google Scholar : PubMed/NCBI


Chakravarthy B, Ménard M, Ito S, Gaudet C, Dal Prà I, Armato U and Whitfield J: Hippocampal membrane-associated p75NTR levels are increased in Alzheimer’s disease. J Alzheimers Dis. 30:675–684. 2012.PubMed/NCBI


Brown EM and MacLeod RJ: Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev. 81:239–297. 2001.PubMed/NCBI


Msaouel P, Nixon AM, Bramos AP, Baiba E and Kentarchos NE: Extracellular calcium-sensing receptor: an overview of physiology, pathophysiology and clinical perspectives. In Vivo. 18:739–753. 2004.PubMed/NCBI


Jensen AA and Bräuner-Osborne H: Allosteric modulation of the calcium-sensing receptor. Curr Neuropharmacol. 5:180–186. 2007. View Article : Google Scholar : PubMed/NCBI


Magno AL, Ward BK and Ratajczak T: The calcium-sensing receptor: a molecular perspective. Endocr Rev. 32:3–30. 2011. View Article : Google Scholar : PubMed/NCBI


Hofer AM and Brown EM: Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol. 4:530–538. 2003. View Article : Google Scholar


Pidasheva S, Grant M, Canaff L, Ercan O, Kumar U and Hendy GN: Calcium-sensing receptor dimerizes in the endoplasmic reticulum: biochemical and biophysical characterization of CaSR mutants retained intracellularly. Hum Mol Genet. 15:2200–2209. 2006. View Article : Google Scholar


Chang W and Shoback D: Extracellular Ca2+-sensing receptors-an overview. Cell Calcium. 35:183–196. 2004.


Ye C, Ho-Pao CL, Kanazirska M, Quinn S, Rogers K, Seidman CE, Seidman JG, Brown EM and Vassilev PM: Amyloid-beta proteins activate Ca(2+)-permeable channels through calcium-sensing receptors. J Neurosci Res. 47:547–554. 1997.


Chiarini A, Dal Prà I, Marconi M, Chakravarthy B, Whitfield JF and Armato U: Calcium-sensing receptor (CaSR) in human brain’s pathophysiology: roles in late-onset Alzheimer’s disease (LOAD). Curr Pharm Biotechnol. 10:317–326. 2009.


Conley YP, Mukherjee A, Kammerer C, DeKosky ST, Kamboh MI, Finegold DN and Ferrel RE: Evidence supporting a role for the calcium-sensing receptor in Alzheimer disease. Am J Med Genet B Neuropsychiatr Genet. 150B:703–709. 2009. View Article : Google Scholar : PubMed/NCBI


Dal Prà I, Chiarini A, Nemeth EF, Armato U and Whitfield JF: Roles of Ca2+ and the Ca2+-sensing receptor (CaSR) in the expression of inducible NOS (nitric oxide synthase)-2 and its BH4 (tetrahydrobiopterin)-dependent activation in cytokine-stimulated adult human astrocytes. J Cell Biochem. 96:428–438. 2005.


Chiarini A, Dal Prà I, Gottardo R, Bortolotti F, Whitfield JF and Armato U: The BH4 (tetrahydrobiopterin)-dependent activation, but not the expression, of inducible NOS (nitric oxide synthase)-2 in proinflammatory cytokine-stimulated, cultured normal human astrocytes is mediated by MEK-ERK kinases. J Cell Biochem. 94:731–743. 2005.


Chiarini A, Dal Prà I, Menapace L, Pacchiana R, Whitfield JF and Armato U: Soluble amyloid β-peptide and myelin basic protein strongly stimulate, alone and in synergism with combined proinflammatory cytokines, the expression of functional nitric oxide synthase-2 in normal adult human astrocytes. Int J Mol Med. 16:801–807. 2005.


Chiarini A, Armato U, Pacchiana R and Dal Prà I: Proteomic analysis of GTP cyclohydrolase 1 multiprotein complexes in cultured normal adult human astrocytes under both basal and cytokine-activated conditions. Proteomics. 9:1850–1860. 2009. View Article : Google Scholar


Chiarini A, Whitfield J, Bonafini C, Chakravarthy B, Armato U and Dal Prà I: Amyloid-β(25–35), an amyloid-β(1–42) surrogate, and proinflammatory cytokines stimulate VEGF-A secretion by cultured, early passage, normoxic adult human cerebral astrocytes. J Alzheimers Dis. 21:915–926. 2010.


Dal Prà I, Whitfileld JF, Pacchiana R, Bonafini C, Talacchi A, Chakravarthy B, Armato U and Chiarini A: The amyloid-β42 proxy, amyloid-β25–35, induces normal human cerebral astrocytes to produce amyloid-β42. J Alzheimers Dis. 24:335–347. 2011.


Nedergaard M, Ransom B and Goldman SA: New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci. 26:523–530. 2003. View Article : Google Scholar : PubMed/NCBI


Nagele RG and Wegiel J, Venkataraman V, Imaki H, Wang KC and Wegiel J: Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging. 25:663–674. 2004.


Nedergaard M and Verkhratsky A: Artefact versus reality-how astrocytes contribute to synaptic events. Glia. 60:1013–1023. 2012. View Article : Google Scholar : PubMed/NCBI


Theodosis DT, Poulain DA and Oliet SH: Activity-dependent structural and functional plasticity of astrocyte-neuron interactions. Physiol Rev. 88:983–1008. 2008. View Article : Google Scholar : PubMed/NCBI


Guenette SY: Astrocytes: a cellular player in Abeta clearance and degradation. Trends Mol Med. 9:279–280. 2003. View Article : Google Scholar : PubMed/NCBI


Biron KE, Dickstein DL, Gopaul R and Jefferies WA: Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer’s disease. PLoS One. 6:e237892011.PubMed/NCBI


Pogue AI and Lukiw WJ: Angiogenic signaling in Alzheimer’s disease. Neuroreport. 15:1507–1510. 2004.


Zand L, Ryu JK and McLarnon JG: Induction of angiogenesis in the beta-amyloid peptide-injected rat hippocampus. Neuroreport. 16:129–132. 2005. View Article : Google Scholar : PubMed/NCBI


Bell RD and Zlokovic BV: Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropatol. 118:103–113. 2008.


Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, Yassa MA, Bassett SS, Shelton AL and Gallagher M: Reduction of hippocampal hyperactivity improves cognition in anamnestic mild cognitive impairment. Neuron. 74:467–474. 2012. View Article : Google Scholar : PubMed/NCBI


Putcha D, Brickhouse M, O’Keefe K, Sullivan C, Rentz D, Marshall G, Dickerson B and Sperling R: Hippocampal hyperactivation associated with cortical thinning in Alzheimer’s disease signature regions in non-demented elderly adults. J Neurosci. 31:17680–17688. 2011.PubMed/NCBI


Sperling R: Potential of functional MRI as a biomarker in early Alzheimer’s disease. Neurobiol Aging. 32(Suppl 1): S37–S43. 2011.


Yassa MA, Stark SM, Bakker A, Albert MS, Gallagher M and Stark CE: High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with anamnestic mild cognitive impairment. Neuroimage. 51:1242–1252. 2010. View Article : Google Scholar : PubMed/NCBI


Jantaratnotai N, Ryu JK, Schwab C, McGeer PL and McLarnon JG: Comparison of vascular perturbations in an Aβ-injected animal model and in AD brain. Int J Alzheimers Dis. 2011:9182802011.PubMed/NCBI


Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ and Hyman BT: Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature. 451:720–724. 2008.PubMed/NCBI


Altman J and Das GD: Postnatal neurogenesis in the guinea-pig. Nature. 214:1098–1101. 1967. View Article : Google Scholar : PubMed/NCBI


Nottebohm F: Testosterone triggers growth of brain vocal control nuclei in adult female canaries. Brain Res. 189:429–436. 1980. View Article : Google Scholar : PubMed/NCBI


Kempermann G: Adult Neurogenesis. 2. Oxford University Press; New York: 2011


Einstein EB, Patterson CA, Hon BJ, Regan KA, Reddi J, Melnikoff DE, Mateer MJ, Schulz S, Johnson BN and Tallent MK: Somatostatin signaling in neuronal cilia is critical for object recognition memory. J Neurosci. 30:4306–4314. 2010. View Article : Google Scholar : PubMed/NCBI


Burgos-Ramos E, Hervás-Aguilar A, Aguado-Liera D, Puebla-Jiménez L, Hernández-Pinto AM, Barrios V and Arilla-Ferreiro E: Somatostatin and Alzheimer’s disease. Mol Cell Endocrinol. 286:104–111. 2008.


Händel M, Schultz S, Stanarius A, Schreff M, Erdtmann-Vourliotis M, Schmidt H, Wolf G and Höllt V: Selective targeting of somatostatin receptor 3 to neuronal cilia. Neuroscience. 89:909–926. 1999.PubMed/NCBI


Stanić D, Malmgren H, He H, Scott L, Aperia A and Hökfelt T: Developmental changes in frequency of the ciliary somatostatin receptor 3 protein. Brain Res. 1249:101–112. 2009.PubMed/NCBI


Berbari NF, Johnson AD, Lewis JS, Askwith CC and Mykytyn K: Identification of ciliary localization sequences within the third intracellular loop of G protein-coupled receptors. Mol Biol Cell. 19:1540–1547. 2008. View Article : Google Scholar : PubMed/NCBI


Goetz SC, Ocbina PJ and Anderson KV: The primary cilium as a hedgehog signal transduction machine. Methods Cell Biol. 94:199–222. 2009. View Article : Google Scholar : PubMed/NCBI


Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY and Reiter JF: Vertebrate smoothened functions at the primary cilium. Nature. 437:1018–1021. 2005. View Article : Google Scholar : PubMed/NCBI


Han YG, Spassky N, Romaguera-Ros M, Garcia-Verdugo JM, Aguilar A, Schneider-Maunoury S and Alvarez-Buylla A: Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci. 11:277–284. 2008. View Article : Google Scholar : PubMed/NCBI


Amador-Arjona A, Elliott J, Miller A, Ginbey A, Pazour GJ, Enikolopov G, Roberts AJ and Terskikh AV: Primary cilia regulate proliferation of amplifying progenitors in adult hippocampus: implications for learning and memory. J Neurosci. 31:9933–9944. 2011. View Article : Google Scholar : PubMed/NCBI


Schaeffer EL, Novaes BA, Da Silva ER, Skaf HD and Mendes-Neto AG: Strategies to promote differentiation of newborn neurons into mature functional cells in Alzheimer brain. Prog Neuropsychopharmacol Biol Psychiatry. 33:1087–1102. 2009. View Article : Google Scholar : PubMed/NCBI


van Tijn P, Kamphuis W, Marlatt MW, Hol EM and Lucassen PJ: Presenilin mouse and zebrafish models for dementia: focus on neurogenesis. Prog Neurobiol. 93:149–164. 2011.PubMed/NCBI


Waldau B and Shetty AK: Behavior of neural stem cells in the Alzheimer brain. Cell Mol Life Sci. 65:2372–2384. 2008. View Article : Google Scholar : PubMed/NCBI


Armato U, Chakravarthy B, Chiarini A, Dal Prà I and Whitfield JF: Is Alzheimer’s disease at least partly a ciliopathy? J Alzheimers Dis. 1:101e2011. View Article : Google Scholar


Gaudet C, Ménard M, Brown L, Atkinson T, LaFerla FM, Ito S, Armato U, Dal Prà I, Whitfield J and Chakravarthy B: Reduction of the immunostainable length of the hippocampal dentate granule cells’ primary cilia in 3xAD-transgenic mice producing human Aβ1–42 and tau. Biochem Biophys Res Commun. September 17–2012.(Epub ahead of print).


Rodríguez JJ, Jones VC, Tabuchi M, Allan SM, Knight EM, LaFerla FM, Oddo S and Verkhratsky A: Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer’s disease. PLoS One. 3:e29352008.PubMed/NCBI


Avila J, Insausti R and Del Rio J: Memory and neurogenesis in aging and Alzheimer’s disease. Aging Dis. 1:30–36. 2010.


Shetty AK: Reelin signaling, hippocampal neurogenesis and efficacy of aspirin intake and stem cell transplantation in aging and Alzheimer’s disease. Aging Dis. 1:2–11. 2010.PubMed/NCBI


Whitfield JF, Chakravarthy B, Chiarini A and Dal Prà I: The primary cilium: The tiny driver of dentate gyral neurogenesis. Neurogenesis Research. Clark GJ and Anderson WT: Chapter V. Nova Science Publishers Inc; Hauppauge, NY: pp. 137–159. 2012, (In press). ISBN: 9781620817230


Fortress AM, Buhusi M, Helke KL and Granholm AC: Cholinergic degeneration and alterations in the TrkA and p75NTR balance as a result of pro-NGF injection into aged rats. J Aging Res. 2011:4605432011. View Article : Google Scholar : PubMed/NCBI


Armato U, Chakravarthy B, Chiarini A, Dal Prà I and Whitfield JF: A Paradigm-changing surprise from dentate gyrus granule cells-cilium-localized p75NTR may drive their progenitor cell proliferation. J Alzheimers Dis. 1:e1042011. View Article : Google Scholar


Pérez-González R, Antequera D, Vargas T, Spuch C, Bolos M and Carro E: Leptin induces the proliferation of neuronal progenitors and neuroprotection in a mouse model of Alzheimer’s disease. J Alzheimers Dis. 24:17–25. 2011.PubMed/NCBI


Armato U, Chakravarthy B, Chiarini A, Chioffi F, Dal Prà I and Whitfield JF: Leptin, sonic hedgehogs and neurogenesis-a primary cilium’s tale. J Alzheimers Dis. 1:e1052012. View Article : Google Scholar


Bianca VD, Dusi S, Bianchini E, Dal Prà I and Rossi F: Beta-amyloid activates the O2-forming NADPH oxidase in microglia, monocytes and neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer’s disease. J Biol Chem. 274:15493–15499. 1999.PubMed/NCBI


Armato U, Bonafini C, Chakravarthy B, Pacchiana R, Chiarini A, Whitfield JF and Dal Prà I: The calcium-sensing receptor: A novel Alzheimer’s disease crucial target? J Neurol Sci. July 27–2012.(Epub ahead of print). View Article : Google Scholar

Related Articles

Journal Cover

January 2013
Volume 31 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
Spandidos Publications style
Armato U, Chakravarthy B, Pacchiana R and Whitfield JF: Alzheimer's disease: An update of the roles of receptors, astrocytes and primary cilia (Review). Int J Mol Med 31: 3-10, 2013
Armato, U., Chakravarthy, B., Pacchiana, R., & Whitfield, J.F. (2013). Alzheimer's disease: An update of the roles of receptors, astrocytes and primary cilia (Review). International Journal of Molecular Medicine, 31, 3-10.
Armato, U., Chakravarthy, B., Pacchiana, R., Whitfield, J. F."Alzheimer's disease: An update of the roles of receptors, astrocytes and primary cilia (Review)". International Journal of Molecular Medicine 31.1 (2013): 3-10.
Armato, U., Chakravarthy, B., Pacchiana, R., Whitfield, J. F."Alzheimer's disease: An update of the roles of receptors, astrocytes and primary cilia (Review)". International Journal of Molecular Medicine 31, no. 1 (2013): 3-10.