Prostacyclin Promotes Degenerative Pathology in a Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the most common form of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression significantly worsened multiple measures associated with amyloid-β (Aβ) disease pathologies. Mice overexpressing both Aβ and PGI2 exhibited impaired learning and memory and increased anxiety-like behavior compared with non-transgenic and PGI2 control mice. PGI2 overexpression accelerated the development of Aβ accumulation in the brain and selectively increased the production of soluble Aβ42. PGI2 damaged the microvasculature through alterations in vascular length and branching; Aβ expression exacerbated these effects. Our findings demonstrate that chronic prostacyclin expression plays a novel and unexpected role that hastens the development of the AD phenotype

Peripheral neuropathic pain : a mechanism-related organizing principle based on sensory profiles

Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of painrelated sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profilesmight respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroupswith characteristic sensory profileswere identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combinationwith pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders.Peer reviewe

The Effect of Heterozygous Loss of Progranulin on Alzheimer's Disease

Haploinsufficient loss of progranulin (PGRN) is implicated in both frontotemporal lobar dementia (FTD) and Alzheimer’s disease (AD). Furthermore, Grn polymorphisms have been linked to various other neurodegenerative diseases suggesting PGRN plays an important role in neurodegenerative disease pathways. Although genetic studies have demonstrated that partial loss of PGRN increases the risk of AD there are conflicting reports in mouse studies examining the loss of PGRN and it is unclear how the loss of PGRN modulates AD pathophysiology. Therefore, the present study was designed to elucidate the effect of haploinsufficiency loss of PGRN on the pathophysiology of AD. To this end, we characterized a novel PGRN haploinsufficient mouse model (Grn+/-) across age. Utilizing a battery of cognitive and non-cognitive behavior tests we observed key FTD-related behavior deficits in Grn+/- mice across age in the absence of FTD-related pathology including neuroinflammation and TDP-43 proteinopathy as measured by immunohistochemical and western blot techniques. We observed functional deficits in Grn+/- mice, including impaired long-term potentiation and reduced numbers of GABAergic interneurons. Next, we investigated the role of haploinsufficiency PGRN loss on tau pathology by crossing Grn+/- mice with the P301S tau transgenic mouse model. There were slight differences in tau-related non-cognitive behavior deficits and reduced AT8 tau phosphorylation in the brain and spinal cord measured by western blot techniques. While we did not observe differences in microglial activation, we observed alterations in the Akt signaling pathway. Lastly, we investigated the role of haploinsufficiency PGRN loss on amyloid pathology by crossing Grn+/- mice with the APdE9 amyloid transgenic mouse model. We observed exacerbated deficits in AD-related cognitive and non-cognitive behavior, including worsened cognitive learning and memory and motor coordination. We also observed biochemical and morphological changes in amyloid pathology. While we did not observe differences in microglial activation, we did observe deficits in synaptic plasticity and loss of GABAergic interneurons with loss of PGRN. In summary, several conclusions can be drawn from the present study. First, heterozygous loss of global progranulin across age replicates critical frontotemporal dementia-related behavioral and functional deficits in the absence of detectable neuroinflammation. Secondly, heterozygous loss of progranulin reduces tau hyperphosphorylation in an Alzheimer’s transgenic mouse model suggesting that loss of progranulin, at least in the context of tau pathology, may be beneficial. Lastly, heterozygous loss of progranulin exacerbates Alzheimer’s disease-related behavior and amyloid-beta pathology in an Alzheimer’s transgenic mouse model, suggesting that loss of progranulin, at least in the context of amyloid pathology, may be detrimental. Our results suggest a dissociation of behavioral and functional deficits from microglial activation, suggesting an essential effect of progranulin deficiency on neurons driving key FTD-related behavioral deficits and potential underlying mechanisms. While progranulin has been suggested to be a potential therapeutic target for Alzheimer’s disease our results suggest this may not be the case due to differential effects on Alzheimer’s’ disease pathology

Microglia in the Alzheimer's brain: a help or a hindrance?

Alzheimer’s disease (AD), the leading cause of dementia, is a complex neurodegenerative disorder. The AD brain is characterized by the presence of Amyloid-β (Aβ) plaques, neurofibrillary tangles, and an increased inflammatory response. Microglia, the chief immune cells of the central nervous system, have been implicated in AD due to their strong association with Aβ plaques. The role of inflammation associated with microglia has been hotly contested in development of Alzheimer’s disease. A growing amount of genetic studies have implicated microglia in late-onset AD and their role in Aβ clearance. Although traditionally microglia have been considered to be either in resting or activated states, these cells are now known to exist in multiple heterogeneous populations and altered roles that appear to impact pathological states of the Alzheimer’s brain

A Novel Liposomal Nanoparticle for the Imaging of Amyloid Plaque by Magnetic Resonance Imaging

Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo. The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy. Upon intravenous injection, the particles successfully traversed the blood-brain barrier in these mice, and bound to the plaques. Magnetic resonance imaging (T1-MRI) conducted 4 days after injection demonstrated elevated signal in the brains of mice with amyloid plaques present. No signal was observed in amyloid-negative mice, or in amyloid-positive mice injected with an untargeted version of the same agent. The MRI results were confirmed by immunohistochemical and fluorescent microscopic examination of mouse brain sections, showing colocalization of the fluorescent tags and amyloid deposits

A Novel Liposomal Nanoparticle for the Imaging of Amyloid Plaque by Magnetic Resonance Imaging

Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo. The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy. Upon intravenous injection, the particles successfully traversed the blood-brain barrier in these mice, and bound to the plaques. Magnetic resonance imaging (T1-MRI) conducted 4 days after injection demonstrated elevated signal in the brains of mice with amyloid plaques present. No signal was observed in amyloid-negative mice, or in amyloid-positive mice injected with an untargeted version of the same agent. The MRI results were confirmed by immunohistochemical and fluorescent microscopic examination of mouse brain sections, showing colocalization of the fluorescent tags and amyloid deposits

Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer.

UNLABELLED: Transcriptionally active ESR1 fusions (ESR1-TAF) are a potent cause of breast cancer endocrine therapy (ET) resistance. ESR1-TAFs are not directly druggable because the C-terminal estrogen/anti-estrogen-binding domain is replaced with translocated in-frame partner gene sequences that confer constitutive transactivation. To discover alternative treatments, a mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) was deployed to identify druggable kinases that are upregulated by diverse ESR1-TAFs. Subsequent explorations of drug sensitivity validated RET kinase as a common therapeutic vulnerability despite remarkable ESR1-TAF C-terminal sequence and structural diversity. Organoids and xenografts from a pan-ET-resistant patient-derived xenograft model that harbors the ESR1-e6>YAP1 TAF were concordantly inhibited by the selective RET inhibitor pralsetinib to a similar extent as the CDK4/6 inhibitor palbociclib. Together, these findings provide preclinical rationale for clinical evaluation of RET inhibition for the treatment of ESR1-TAF-driven ET-resistant breast cancer. SIGNIFICANCE: Kinome analysis of ESR1 translocated and mutated breast tumors using drug bead-based mass spectrometry followed by drug-sensitivity studies nominates RET as a therapeutic target. See related commentary by Wu and Subbiah, p. 3159