The enormous, 2–3-million-year evolutionary expansion of hominin neocortices to the current enormity enabled humans to take over the planet. However, there appears to have been a glitch, and it occurred without a compensatory expansion of the entorhinal cortical (EC) gateway to the hippocampal memory-encoding system needed to manage the processing of the increasing volume of neocortical data converging on it. The resulting age-dependent connectopathic glitch was unnoticed by the early short-lived populations. It has now surfaced as Alzheimer’s disease (AD) in today’s long-lived populations. With advancing age, processing of the converging neocortical data by the neurons of the relatively small lateral entorhinal cortex (LEC) inflicts persistent strain and high energy costs on these cells. This may result in their hyper-release of harmless Aβ1–42 monomers into the interstitial fluid, where they seed the formation of toxic amyloid-β oligomers (AβOs) that initiate AD. At the core of connectopathic AD are the postsynaptic cellular prion protein (PrPC). Electrostatic binding of the negatively charged AβOs to the positively charged N-terminus of PrPC induces hyperphosphorylation of tau that destroys synapses. The spread of these accumulating AβOs from ground zero is supported by Aβ’s own production mediated by target cells’ Ca2+-sensing receptors (CaSRs). These data suggest that an early administration of a strongly positively charged, AβOs-interacting peptide or protein, plus an inhibitor of CaSR, might be an effective AD-arresting therapeutic combination.

We have recently demonstrated the brain-delivery of an Amyloid-ß oligomer (Aßo)-binding peptide-therapeutic fused to the BBB-crossing single domain antibody FC5. The bi-functional fusion protein, FC5-mFc-ABP (KG207-M) lowered both CSF and brain Aß levels after systemic dosing in transgenic mouse and rat models of Alzheimer’s disease (AD). For development as a human therapeutic, we have humanized and further engineered the fusion protein named KG207-H. The purpose of the present study was to carry out comparative PK/PD studies of KG207-H in wild type rat and beagle dogs (middle-aged and older) to determine comparability of systemic PK and CSF exposure between rodent species and larger animals with more complex brain structure such as dogs. Beagle dogs were used in this study as they accumulate cerebral Aß with age, as seen in human AD patients, and can serve as a model of sporadic AD. KG207-H (5 to 50 mg/kg) was administered intravenously and serum and CSF samples were serially collected for PK studies and to assess target engagement. KG207-H and Aβ levels were quantified using multiplexed selected reaction monitoring mass spectrometry. After systemic dosing, KG207-H demonstrated similar serum pharmacokinetics in rats and dogs. KG207-H appeared in the CSF in a time- and dose-dependent manner with similar kinetics, indicating CNS exposure. Further analyses revealed a dose-dependent inverse relationship between CSF KG207-H and Aß levels in both species indicating target engagement. This study demonstrates translational attributes of BBB-crossing Aβ-targeting biotherapeutic KG207-H in eliciting a pharmacodynamic response, from rodents to larger animal species.

Introduction: Patients with COPD often have complex needs and multiple co-morbidities. Some need nutritional support; many still smoke. Pulmonary Rehabilitation(PR) improves those who complete it. Immunisation for influenza and pneumonia work; good inhaler technique is essential. For those in hospital with exacerbations early discharge is possible; use of a discharge bundle with community referral increases service access. We provide community in-reach to the admission areas, review after discharge, PR, and oxygen services and work closely together with hospital colleagues. Methods: We carried out nested audits to examine our referrals, changes to admissions, potential for interventions and patients with frequent admissions. Results: In 2017 referrals were 997, 64% after in-patient stay. Patients have severe disease,7.6% NIV/CPAP. 17% oxygen, 25% nebulised therapy: 21% smoke, 5.5% BMI<18. 2015-7 In reach to admission areas saw 463 patients, 149 discharged<24hr; Length of stay fell 2013-4 v 2016-7, 7.6 v 5.9days. More in-patients are now known to service, 30% 2015, 76% 2017. A discharge bundle including community referral use in 59%, Jan2015: 95% 2017. In 66 high risk patients with 3 or more admissions/yr in 2015-6 41% died <6mo; after identification/interventions admissions fell in 6/12 after v 6/12 before, 124 v 56, P<0.001, hospital days 899 v 486, P<0.001. In 2016-7, 44 further patients showed reduction in admissions (107 v 54, P<0.001:days 838 v 298, P<0.05. In the later group 27% BMI<18 all had nutrition support,23% azithromycin and 41% PR; 30% smokers. Conclusions: A focus on identifying potential interventions leads to less hospital load even in those with severe disease.

Understanding the pathophysiology of Alzheimer's disease (AD) in the principal human neural cells is necessary for finding therapeutics for this illness. To help do this, we have been using freshly cultured functionally normal cerebral cortical adult human astrocytes (NAHAs) and postnatal neurons. The findings show that amyloid-β oligomers (Aβ-os) binding to calcium-sensing receptors (CaSRs) on NAHAs and neuron surfaces trigger signals capable of driving AD pathogenesis. This Aβ•CaSR signalling shifts the amyloid precursor protein (APP) from its α-secretase shedding producing neurotrophic/neuroprotective soluble (s)APPα to its β-secretase cleaving engendering AD-driving Aβ42/Aβ42-os peptides. Aβ•CaSR signalling in NAHAs also drives the release of toxic hyper-phosphorylated Tau proteins in exosomes, and of nitric oxide, and VEGF-A. These several harmful agents comprise the neuron-killing machinery, driving the very slowly spreading AD neurocontagion. VEGF-A over-secretion from Aβ-exposed blood vessel-attached astrocytes induces a functional magnetic resonance imaging- detectable hippocampal neoangiogenesis which indicates approaching AD in amnestic minor cognitive impairment (aMCI) patients. Most important in AD's regard, selective allosteric CaSR antagonists (calcylitics) added to Aβ42/Aβ42-os-exposed NAHAs (or to human neuron cultures) rescue the extracellular shedding of neurotrophic/ neuroprotective sAPPα and suppress all the neurotoxic effects of Aβ•CaSR signalling even when multiple microglial cytokines are also present. Therefore, since the multipotent calcilytics would be reasonably safe and inexpensive drugs for humans, it is worthwhile testing them as AD therapeutics in clinical trials especially in persons in the earliest detectable stages of AD neuropathology progression such as aMCI.

We serve 450,000 people in Essex, UK, with close integration between community and hospital based respiratory teams, referral to community team as part of the discharge process bundle, pulmonary rehabilitation, oxygen services, and regular review of COPD patients in the community. Community based nurses visit the hospital for in-reach to facilitate early discharge. Patients with severe disease are discussed at a multi-disciplinary MDT. Methods: We carried out a series of nested audits to examine the clinical characteristics of our patients, the effect of nurse in-reach and the effect of an integrated approach on admissions and length of stay. Results: In 2016 there were 1234 referrals to the community team. 95% with COPD. There were 459 oxygen and 586 direct pulmonary rehabilitation referrals. In 2015-6 compared to 2014-5 the activities of the integrated team lead to a reduction in admissions from 841-774 (8.4%) This has continued into 2016-7 with April to October admissions for 2014 of 367, 2015, 320, and 2016, 329. This is a 10.4% drop between 2014-6. Length of stay 2014 was 7.4 days; 2015: 6.1 days. In 2016 nurse in-reach saw 323 patients, 285 in A&E or acute admission wards and 38 elsewhere. 264 were identified as suffering from COPD; 109 patients were discharged that day. Referral to the community team as part of the discharge bundle occurred in 87.4% of patients discharged alive from our area. Conclusion: Integration of community and hospital respiratory teams with use of a robust discharge process and access to community PR and oxygen services leads to reduction in admissions and appropriate care for patients with COPD.

We have identified an amyloid-ß (Aß) binding peptide (ABP) that selectively bound pathological Aß1–42 oligomers and reduced Aß- mediated cell toxicity1. ABP also bound Aß deposits in brains of AD transgenic mice and Alzheimer's disease (AD) patients in vitro, and when directly injected into live transgenic mice (APPSwe and ΔPS1) brain2, suggesting that, when delivered to the brain, ABP can engage Aß and facilitate its clearance. Present study shows brain-delivery of ABP by a novel BBB-crossing domain antibody, and targeting and clearance of Aß in transgenic mice. Recombinant ABP-BBB carrier fusion construct (ABP-BBB) were produced in CHO cells. BBB-permeability of the construct was assessed using in vitro BBB (formed by rat or human brain endothelial cells) and in vivo (rat and mouse) models. Aß binding was determined by ELISA and Western blot overlay assays. For PK/PD studies, serum, CSF and brain levels of ABP-BBB construct and Aß were assessed following iv injection by nanoLC- MRM, ELISA and Western blot methods. ABP-BBB bi-functional fusion protein was successfully expressed in CHO cells. The fusion protein retained both Aß-oligomer binding activity and BBB-permeability in vitro. ABP-BBB transmigrated the in vitro BBB, in contrast to ABP without BBB carrier. When injected iv into rats, ABP-BBB appeared in the CSF in a dose- and time-dependent manner indicating transport of ABP across BBB in vivo. Apparent CNS exposure (Expapp), calculated as CSF[AUC]/serum[AUC], indicated a 15–20-fold increase in Expapp for ABP-BBB compared to non-BBB permeable ABP. This was further confirmed in mouse model wherein following iv injection, the fusion protein was detected in the CSF, and cortical and hippocampal regions of wild type and Tg mice. More importantly, in Tg mice ABP treatment resulted in a significant (∼50%) reduction of Aß levels in the CSF, and brain cortex and hippocampus within 4-weeks. Collectively, these results indicate that the novel BBB carrier can deliver otherwise BBB-impermeable ABP to the brain where it can target CNS Aß aggregates and facilitate their clearance in vivo. 1 Chakravarthy et al., J. Neurochem 126, 415, 2013. 2 Chakravarthy et al., Biochem. Biophys. Res. Commun. 445, 656, 2014.

To identify the impact of a community integrated respiratory team on early discharge after exacerbation of COPD, need for pulmonary rehabilitation and care provision in the community. A rolling audit of all referrals to the team to identify comorbidity, complexity of disease and need for pulmonary

Introduction: Integration of community respiratory care including pulmonary rehabilitation (PR) and oxygen services with hospital based care and in-reach into the acute hospital by the community team has the potential for early discharge and increased PR. Methods: We have carried out a series of nested audits into the use of a discharge bundle and the effect of community respiratory team in-reach into an acute hospital serving a population of 450,000 and the rate of uptake and referral for PR for these patients. Results: During 2015 there were 1420 referrals to the community respiratory team, 773 from hospital, and 647 from primary care. 98% had COPD. Average co-morbidity rate was 2.6/patient, 27% >3. In January 2015 only 59% of in patients were referred to the community team, but by May/June 75%, and Sept-Nov 2015 85%. Community in-reach reviewed 207 patients in 2015, 27% of those with COPD were discharged the same day. From Apr2015-Feb 2016 701 patients were referred for PR v 300 for PR in all of2014-5.501 were referred fro oxygen services. Over years hospital rates of admission for COPD have been rising, 2012-3v2014-5 789v839. But since the start of the integrated service admissions have fallen, Jan-June 2014 v 2015, 404 v 390, (4%); Sept-Nov 2014 v 2015, 210 v 197, (6.2%). Length of stay has also fallen, April-Oct 2014 v 2015; 7.4 v 6.1 days which may reflect early discharge practices. Conclusion: A respiratory service integrated between hospital and community including PR and oxygen services leads to higher rates of referral for PR , and less admissions with shorter length of stay when previously admission rates were steadily climbing.

We have previously shown in SH-SY5Y human neuroblastoma cells that the expressions of basal (75 kDa) and high molecular weight (HMW; 85 kDa) isoforms of the p75 neurotrophic receptor (p75NTR) are stimulated by amyloid-beta peptidel-42 oligomers (A beta Os) via the insulin-like growth factor-1 receptor (IGF-1R). On the other hand, it is known that A beta Os inhibit insulin receptor (IR) signaling. The purpose of the present study was to determine the involvement of IR signaling in the regulation of p75 neurotrophin receptor (p75NTR) protein isoform expression in cultured SH-SY5Y cells and in hippocampi from late stage human Alzheimer's disease (AD) brains. Interestingly, insulin induced the expression of basal and HMW p75NTR isoforms in SH-SY5Y cells, suggesting the presence of cross-talk between the IR and IGF-1R for the regulation of p75NTR expression. Reducing IR signaling with an IR kinase inhibitor (AG 1024) or IR-targeted siRNAs increased HMW p75NTR expression and reduced tyrosine receptor kinase-A (Trk-A) expression as well as postsynaptic density protein 95 (PSD95) expression in SH-SY5Y cells. Both basal and HMW p75NTR isoforms were increased in the hippocampi of post-mortem late-stage human AD brains (relative to non-AD brains), and the protein expression of HMW p75NTR was negatively associated with Trk-A expression, PSD95 expression, and IR expression. Thus, increased p75NTR expression, specifically an increased p75NTR-to-Trk-A ratio, is likely to play a role in synaptic loss and neuronal cell death in late-stage AD. Collectively, these findings suggest that increased expression of the p75NTR due to IR signaling inhibition by A beta Os might be involved in the pathology of AD. (C) 2016 Elsevier Ltd. All rights reserved.

The "amyloid cascade hypothesis" posits that an extracellular build-up of amyloid-β oligomers (Aβ-os) and polymers (fibrils) subsequently inducing toxic hyperphosphorylated (p)-Tau oligomers (p-Tau-os) and neurofibrillary tangles starts the sporadic late-onset Alzheimer's disease (LOAD) in the aged lateral entorhinal cortex. Conversely, mutated genes cause a diffuse cerebral Aβs/Aβ-os overproduction promoting early-onset familiar AD (EOFAD). Surplus exogenous Aβ-os exert toxic actions at several levels. They reach the nuclei of human astrocyte-neurons teams (ANTs) to enhance the transcription of Aβ precursor protein (APP) and β-secretase/BACE1 genes. The overexpressed APP and BACE1 proteins act in concert with γ-secretase to overproduce endogenous Aβs/Aβ-os, of which a few enter the nuclei to upkeep Aβs overproduction, while the rest gather in the cytoplasm, damage mitochondria, and are oversecreted. Simultaneously, extracellular Aβ-os bind the ANTs' calcium-sensing receptors (CaSRs) activating signalings that hinder the proteolysis and hence favor the surplus hoarding/secretion of Aβs/Aβ-os. Overreleased Aβ-os spread, reach growing numbers of adjacent ANTs to recruit them to overproduce/oversecrete further Aβ-os amounts via the just mentioned mechanisms. Alongside, Aβ•CaSR signalings elicit a noxious overproduction/overrelease of nitric oxide (NO) and vascular endothelial growth factor (VEGF)-A from ANTs' astrocytes. While astrocytes survive the toxic onslaught, neurons die. Thus, AD progression is driven by ceaselessly self-sustaining neurotoxic cycles, which engender first Aβ-os and later p-Tau-os that cooperatively destroy increasingly wider cognition-related cortical areas. Notably, a highly selective allosteric CaSR antagonist (calcilytic), like NPS 2143, does preserve human cortical postnatal HCN-1A neurons viability notwithstanding the presence of exogenous Aβ-os by suppressing the otherwise elicited oversecretion and spread of newly synthesized Aβ-os. Therefore, if given at minimal cognitive impairment or earlier stages, calcilytics could halt AD progression and preserve the patients' cortical neurons, cognitive abilities, and eventually life.

Dentate-gyral granule cells in the hippocampus plus dentate gyrus memory-recording/retrieving machine, unlike most other neurons in the brain, are continuously being generated in the adult brain with the important task of separating overlapping patterns of data streaming in from the outside world via the entorhinal cortex. This “adult neurogenesis” is driven by tools in the mature granule cell’s cilium. Here we report our discovery of leptin’s LepRb receptor in this cilium. In addition, we discuss how ciliary LepRb signaling might be involved with ciliary p75NTR and SSTR3 receptors in adult neurogenesis and memory formation as well as attenuation of Alzheimer’s neuropathology by reducing the production of its toxic amyloid-β-derived drivers.

Evidence has begun emerging for the "contagious" and destructive Aβ42 (amyloid-beta42) oligomers and phosphorylated Tau oligomers as drivers of sporadic Alzheimer's disease (AD), which advances along a pathway starting from the brainstem or entorhinal cortex and leading to cognition-related upper cerebral cortex regions. Seemingly, Aβ42 oligomers trigger the events generating the neurotoxic Tau oligomers, which may even by themselves spread the characteristic AD neuropathology. It has been assumed that only neurons make and spread these toxic drivers, whereas their associated astrocytes are just janitorial bystanders/scavengers. But this view is likely to radically change since normal human astrocytes freshly isolated from adult cerebral cortex can be induced by exogenous Aβ25-35, an Aβ42 proxy, to make and secrete increased amounts of endogenous Aβ42. Thus, it would seem that the steady slow progression of AD neuropathology along specific cognition-relevant brain networks is driven by both Aβ42 and phosphorylated Tau oligomers that are variously released from increasing numbers of "contagion-stricken" members of tightly coupled neuron-astrocyte teams. Hence, we surmise that stopping the oversecretion and spread of the two kinds of "contagious" oligomers by such team members, perhaps via a specific CaSR (Ca(2+)-sensing receptor) antagonist like NPS 2143, might effectively treat AD.

The excess vascular endothelial growth factor (VEGF) produced in the Alzheimer’s disease (AD) brain can harm neurons, blood vessels, and other components of the neurovascular units (NVUs). But could astrocytes partaking in networks of astrocyte-neuron teams and connected to blood vessels of NVUs contribute to VEGF production? We have shown with cultured cerebral cortical normal (i.e., untransformed) adult human astrocytes (NAHAs) that exogenous amyloid-β peptides (Aβs) stimulate the astrocytes to make and secrete large amounts of Aβs and nitric oxide by a mechanism mediated through the calcium-sensing receptor (CaSR). Here, we report that exogenous Aβs stimulate the NAHAs to produce and secrete even VEGF-A through a CaSR-mediated mechanism. This is indicated by the ability of Aβs to specifically bind the CaSR, and the capability of a CaSR activator, the “calcimimetic” NPS R-568, to imitate, and of the CaSR antagonist, “calcilytic” NPS 2143, to inhibit, the Aβs stimulation of VEGF-A production and secretion by the NAHAs. Thus, Aβs that accumulate in the AD brain may make the astrocytes that envelop and functionally collaborate with neurons into multi-agent AD-driving “machines” via a CaSR signaling mechanism(s). These observations suggest the possibility that CaSR allosteric antagonists such as NPS 2143 might impede AD progression.

The synthetic ~5 kDa ABP (amyloid-ß binding peptide) consists of a region of the 228 kDa human pericentrioloar material-1 (PCM-1) protein that selectively and avidly binds in vitro Aβ1-42 oligomers, believed to be key co-drivers of Alzheimer's disease (AD), but not monomers (Chakravarthy et al., (2013) [3]). ABP also prevents Aß1-42 from triggering the apoptotic death of cultured human SHSY5Y neuroblasts, likely by sequestering Aß oligomers, suggesting that it might be a potential AD therapeutic. Here we support this possibility by showing that ABP also recognizes and binds Aβ1-42 aggregates in sections of cortices and hippocampi from brains of AD transgenic mice and human AD patients. More importantly, ABP targets Aβ1-42 aggregates when microinjected into the hippocampi of the brains of live AD transgenic mice.

We have recently reported that a similar to 19-kDa polypeptide, rPK-4, is a protein kinase Cs inhibitor that is 89% homologous to the 1171-1323 amino acid region of the 228-kDa human pericentriolar material-1 (PCM-1) protein (Chakravarthy etal. 2012). We have now discovered that rPK-4 binds oligomeric amyloid- peptide (A)(1-42) with high affinity. Most importantly, a PCM-1-selective antibody co-precipitated A and amyloid precursor protein (APP) from cerebral cortices and hippocampi from AD (Alzheimer's disease) transgenic mice that produce human APP and A(1-42), suggesting that PCM-1 may interact with amyloid precursor protein/A in vivo. We have identified rPK-4s A-binding domain using a set of overlapping synthetic peptides. We have found with ELISA, dot-blot, and polyacrylamide gel electrophoresis techniques that a similar to 5kDa synthetic peptide, amyloid binding peptide (ABP)-p4-5 binds A(1-42) at nM levels. Most importantly, ABP-p4-5, like rPK-4, appears to preferentially bind A(1-42) oligomers, believed to be the toxic AD-drivers. As expected from these observations, ABP-p4-5 prevented A(1-42) from killing human SH-SY5Y neuroblastoma cells via apoptosis. These findings indicate that ABP-p4-5 is a possible candidate therapeutic for AD.

The “amyloid-β (Aβ) hypothesis” posits that accumulating Aβ peptides (Aβs) produced by neurons cause Alzheimer's disease (AD). However, the Aβs contribution by the more numerous astrocytes remains undetermined. Previously we showed that fibrillar (f)Aβ25–35, an Aβ42 proxy, evokes a surplus endogenous Aβ42 production/accumulation in cortical adult human astrocytes. Here, by using immunocytochemistry, immunoblotting, enzymatic assays, and highly sensitive sandwich ELISA kits, we investigated the effects of fAβ25–35 and soluble (s)Aβ25–35 on Aβ42 and Aβ40 accumulation/secretion by human cortical astrocytes and HCN-1A neurons and, since the calcium-sensing receptor (CaSR) binds Aβs, their modulation by NPS 2143, a CaSR allosteric antagonist (calcilytic). The fAβ25–35-exposed astrocytes and surviving neurons produced, accumulated, and secreted increased amounts of Aβ42, while Aβ40 also accrued but its secretion was unchanged. Accordingly, secreted Aβ42/Aβ40 ratio values rose for astrocytes and neurons. While slightly enhancing Aβ40 secretion by fAβ25–35-treated astrocytes, NPS 2143 specifically suppressed the fAβ25–35-elicited surges of endogenous Aβ42 secretion by astrocytes and neurons. Therefore, NPS 2143 addition always kept Aβ42/Aβ40 values to baseline or lower levels. Mechanistically, NPS 2143 decreased total CaSR protein complement, transiently raised proteasomal chymotrypsin activity, and blocked excess NO production without affecting the ongoing increases in BACE1/β-secretase and γ-secretase activity in fAβ25–35-treated astrocytes. Compared to fAβ25–35, sAβ25–35 also stimulated Aβ42 secretion by astrocytes and neurons and NPS 2143 specifically and wholly suppressed this effect. Therefore, since NPS 2143 thwarts any Aβ/CaSR-induced surplus secretion of endogenous Aβ42 and hence further vicious cycles of Aβ self-induction/secretion/spreading, calcilytics might effectively prevent/stop the progression to full-blown AD.

Alzheimer's disease (AD) is the most common human neurodegenerative ailment, the most prevalent (>95%) late-onset type of which has a still uncertain etiology. The progressive decline of cognitive functions, dementia, and physical disabilities of AD is caused by synaptic losses that progressively disconnect key neuronal networks in crucial brain areas, like the hippocampus and temporoparietal cortex, and critically impair language, sensory processing, memory, and conscious thought. AD's two main hallmarks are fibrillar amyloid-β (fAβ) plaques in extracellular spaces and intracellular accumulation of fAβ peptides and neurofibrillary tangles (NFTs). It is still undecided whether either or both these AD hallmarks cause or result from the disease. Recently, the dysregulation of calcium homeostasis has been advanced as a novel cause of AD. In this case, a suitable candidate of AD driver would be the Aβ peptides–binding/activated calcium-sensing receptor (CaSR), whose intracellular signalling is triggered by Aβ peptides. In this review, we briefly discuss CaSR's roles in normal adult human astrocytes (NAHAs) and their possible impacts on AD.

Reportedly, astrocytes gap-junctionally interconnected with neurons enwrap synapses to form “tripartite synapses” and their products directly impact on synaptic signalling. Until recently, astrocytes were thought to act just as janitors sweeping up any Aβ peptides released by neurons in AD brains. Here, we present evidence that astrocytes' role is much more complex and important as they are involved in the development of AD. Normal adult human astrocytes (NAHAs) isolated from tissue fragments of temporal lobe cortex of patients with perforating head trauma were set into cultures and used experimentally in their early passages. Cultures were treated with Aβ(25–35) or reverse Aβ(35–25) for up to 72 hrs. Protein lysates and conditioned growth media were sampled every 24 hrs. Aβ(1–42) levels were assayed by immunoblotting in lysates and via ELISA in medium samples. UPS (ubiquitin-proteasome system) enzyme activities were assessed by standard biochemical methods. The administration of the Aβ(1–42) surrogate Aβ(25–35) induced normal human adult astrocytes to produce and secrete significant amounts of Aβ(1–42) peptides extracellularly. Reverse Aβ(35–25) was instead totally inactive.This increased production/release of Aβ peptides was due to a reduced activity of the UPS (ubiquitin-proteasome system) caused by an Aβ(25–35)-stimulated CaSRs' (Calcium-Sensing Receptors') signaling. In fact, the calcilytic (CaSR-inhibitor) NPS-2143 agent reactivated the UPS activity, which destroyed the low molecular weight Aβ peptides otherwise produced in excess and hence totally suppressed their extracellular secretion by the astrocytes. These results indicate that in AD brains the astrocytes are stimulated by exogenously accumulating Aβ peptides to make Aβ(1–42) and can dump these endogenous toxic oligomers directly onto the neuronal synapses they enwrap, triggering synaptic destruction. Indeed, we have shown that the Aβ peptides released by astrocytes can kill neurons but not their astrocyte producers. Moreover, since there are 10 times more cerebral astrocytes than neurons, the Aβ oligomers they hugely produce/release could, just like “infectious agents”, spread widely and “infect”increasing numbers of neurons and astrocytes, both of which would also start producing/releasing Aβ. This self-sustaining mounting “contagion” may explain the inexorable advance of AD. Hence, calcilytics originally intended to cure osteoporosis would likely stop human AD progression.