- Email: [email protected]
Amyloid pet imaging: prime 1b study
Abstracts / Neurobiology of Aging 39 (2016) S1eS31
ANTI-TAU THERAPY - IS IT THE ANSWER? Eva-Maria Mandelkow. DZNE, Bonn, Germany. E-mail: [email protected] Abnormal changes in tau protein are hallmarks of several neurodegenerative diseases and conditions, termed tauopathies, including AD, FTD, PSP, CBD and even PD, HD, or TBE. Therefore, the prevention or correction of tau abnormalities is a key goal of current research. Approaches to tau-based therapy can take a variety of forms: Reduction of tau protein (e.g. by scavenging antibodies, or by activating proteasomal or autophagic degradation), reduction of tau expression (by antisense oligonucleotides), correction of abnormal tau conformations (via chaperones), correction of abnormal posttranslational modifications (phosphorylation, acetylation, etc.), inhibition of abnormal tau aggregation (by small molecule inhibitors, inhibitory peptides), compensation of the loss of cellular functions (e.g. stabilization of microtubules via small molecule MT binders or peptides), or by inhibiting the trans-cellular spreading of tau pathology in the brain. The presentation will give a brief overview of these approaches and focus on some promising examples. Supported by DZNE, MPG, Tau Consortium. Keywords. Aggregation, Aggregation inhibitor, Antibodies, Tauopathy, Tau, Therapy
DYSTROPHIC NEURITES ARE SITES OF MICROTUBULE DISRUPTION, BACE1 ELEVATION, AND INCREASED Ab GENERATION: THE POTENTIAL ROLE OF Ab OLIGOMERS Robert J. Vassar. Northwestern University, Chicago, IL. E-mail: [email protected] Alzheimer’s disease (AD) is characterized by amyloid plaques composed of the b-amyloid (Ab) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the b-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Ab generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Ab may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Ab, particularly neurotoxic Ab42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Ab42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations and voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors kinesin and dynein were aberrantly localized in peri-plaque dystrophies, as were other neuronal proteins. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Ab generation. Our study supports the hypothesis that Ab oligomers emanating from the plaque induce microtubule disruption in presynaptic dystrophic neurites, thus impairing axonal transport and leading to accumulation of BACE1, exacerbation of amyloid pathology, and AD pathogenesis.
S25
1
Neurimmune, Schlieren, Switzerland; 2 Biogen, Cambridge, USA; 3 University of Zurich, Zurich, Switzerland; 4 University of Zurich, Schlieren, Switzerland. E-mail: [email protected]
Neurodegenerative diseases including Alzheimer’s disease are characterized by abnormal protein aggregation in the central nervous system. The presence of plasma antibodies against such protein aggregates suggests active humoral immune responses along with the formation of B cell memory. We hypothesized that selected B-cell clones triggered by neo-epitopes present in pathological protein aggregates encode antibodies with clearance activities. To test this hypothesis, we screened repertoires of human memory B cells for reactivity against aggregated Ab, tau, a-synuclein, TAR DNA-binding protein 43, and superoxide dismutase 1 and cloned and recombinantly expressed monoclonal antibodies that reacted with the corresponding protein aggregates. For a subset of the resulting recombinant antibodies, preferred binding to the pathologic, misfolded or aggregated form of the cognate peptide over its physiological form was observed, whereas others bound both the physiologic monomeric forms in addition to the pathologic aggregates. Aducanumab, a high affinity human antibody against b-amyloid selectively targets soluble oligomeric peptides and insoluble b-amyloid fibrils with absent binding to monomeric soluble Ab. In transgenic mice with brain b-amyloid pathology, aducanumab diffused across the blood-brain-barrier, accumulated on both diffuse and compact parenchymal Ab deposits, and dose-dependently reduced brain b-amyloid load without affecting cerebrovascular amyloid deposits. In a Phase 1b study in patients with prodromal or mild Alzheimer’s disease aducanumab demonstrated an acceptable safety profile and produced a dose- and time-dependent reduction of amyloid plaque in the brain and a dose-dependent effect of slowing clinical decline. Aducanumab is currently being investigated in two Phase 3 trials in patients with early Alzheimer’s disease. Other such human antibodies developed with the same platform with favorable binding and biological activities are in early clinical or progressed preclinical development as candidate therapeutics for a-synucleinopathies, tauopathies and amyotrophic lateral sclerosis. Keywords. Aggregation, Alzheimer therapy, Amyloid beta, Antibodies, Immunotherapy
AMYLOID PET IMAGING: PRIME 1B STUDY Jeff Sevigny, Joyce Suhy, Ping Chiao, Tianle Chen, Gregory Klein, Derk Purcell, Joonmi Oh, Ajay Verma, Mehul Sampat, Jerome Barakos. N/A, N/A. E-mail: [email protected] Amyloid PET imaging is being investigated as a screening tool to identify amyloid-positive patients as an enrichment strategy for Alzheimer’s disease (AD) clinical trial enrollment. In a multicenter, Phase 1b trial, patients meeting clinical criteria for prodromal or mild AD underwent florbetapir PET scanning at screening. PET, MRI, and co-registered PET/MRI scans were reviewed by 2 independent readers and binary visual readings tabulated. Semi-quantitative values of cortical to whole cerebellar standard uptake value ratios were computed (threshold 1.10). Of 278 patients with an evaluable PET scan, 170 (61%) and 185 (67%) were amyloid-positive by visual reading and quantitative analysis, respectively; 39% were excluded from the study due to an amyloid-negative scan based on visual readings. More ApoE ε4 carriers than non-carriers were amyloid-positive (80% vs 43%). Comparison of visual readings with quantitative results identified 21 discordant cases (92% agreement). Inter- and intra-reader agreements from visual readings were 98% and 100%, respectively. Amyloid PET imaging is an effective and feasible screening tool for enrollment of amyloid-positive patients with early stages of AD into clinical trials.
Keywords. Amyloid, Axonal transport, Ab oligomers, BACE1, Dystrophic neurite, Microtubule
Keywords. Amyloid-PET, PET, Imaging
HUMAN-DERIVED MONOCLONAL ANTIBODIES FOR ALZHEIMER’S DISEASE AND RELATED PROTEINOPATHIES
LANDSCAPE OF ANTIBODY IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE
Jan Grimm1, Thierry Bussiere2, Paul Weinreb2, Marcel Maier1, Robert Dunstan2, Fang Qian2, Mahin Arastu2, Sowmya Chollate2, Melanie Brennan2, Omar Quintero-Monzon2, Robert Scannevin2, H. Arnold2, Thomas Engber2, Kenneth Rhodes2, Christoph Hock3, Alfred Sandrock2, Roger Nitsch4.
Christoph Hock1, Jan Grimm2, Jeff Sevigny2, Roger Nitsch3, Alfred Sandrock2. 1 University of Zurich, Zurich, Switzerland; 2 N/A, N/A; 3 University of Zurich, Schlieren, Switzerland. E-mail: [email protected]
ANTI-TAU THERAPY - IS IT THE ANSWER? Eva-Maria Mandelkow. DZNE, Bonn, Germany. E-mail: [email protected] Abnormal changes in tau protein are hallmarks of several neurodegenerative diseases and conditions, termed tauopathies, including AD, FTD, PSP, CBD and even PD, HD, or TBE. Therefore, the prevention or correction of tau abnormalities is a key goal of current research. Approaches to tau-based therapy can take a variety of forms: Reduction of tau protein (e.g. by scavenging antibodies, or by activating proteasomal or autophagic degradation), reduction of tau expression (by antisense oligonucleotides), correction of abnormal tau conformations (via chaperones), correction of abnormal posttranslational modifications (phosphorylation, acetylation, etc.), inhibition of abnormal tau aggregation (by small molecule inhibitors, inhibitory peptides), compensation of the loss of cellular functions (e.g. stabilization of microtubules via small molecule MT binders or peptides), or by inhibiting the trans-cellular spreading of tau pathology in the brain. The presentation will give a brief overview of these approaches and focus on some promising examples. Supported by DZNE, MPG, Tau Consortium. Keywords. Aggregation, Aggregation inhibitor, Antibodies, Tauopathy, Tau, Therapy
DYSTROPHIC NEURITES ARE SITES OF MICROTUBULE DISRUPTION, BACE1 ELEVATION, AND INCREASED Ab GENERATION: THE POTENTIAL ROLE OF Ab OLIGOMERS Robert J. Vassar. Northwestern University, Chicago, IL. E-mail: [email protected] Alzheimer’s disease (AD) is characterized by amyloid plaques composed of the b-amyloid (Ab) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the b-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Ab generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Ab may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Ab, particularly neurotoxic Ab42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Ab42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations and voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors kinesin and dynein were aberrantly localized in peri-plaque dystrophies, as were other neuronal proteins. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Ab generation. Our study supports the hypothesis that Ab oligomers emanating from the plaque induce microtubule disruption in presynaptic dystrophic neurites, thus impairing axonal transport and leading to accumulation of BACE1, exacerbation of amyloid pathology, and AD pathogenesis.
S25
1
Neurimmune, Schlieren, Switzerland; 2 Biogen, Cambridge, USA; 3 University of Zurich, Zurich, Switzerland; 4 University of Zurich, Schlieren, Switzerland. E-mail: [email protected]
Neurodegenerative diseases including Alzheimer’s disease are characterized by abnormal protein aggregation in the central nervous system. The presence of plasma antibodies against such protein aggregates suggests active humoral immune responses along with the formation of B cell memory. We hypothesized that selected B-cell clones triggered by neo-epitopes present in pathological protein aggregates encode antibodies with clearance activities. To test this hypothesis, we screened repertoires of human memory B cells for reactivity against aggregated Ab, tau, a-synuclein, TAR DNA-binding protein 43, and superoxide dismutase 1 and cloned and recombinantly expressed monoclonal antibodies that reacted with the corresponding protein aggregates. For a subset of the resulting recombinant antibodies, preferred binding to the pathologic, misfolded or aggregated form of the cognate peptide over its physiological form was observed, whereas others bound both the physiologic monomeric forms in addition to the pathologic aggregates. Aducanumab, a high affinity human antibody against b-amyloid selectively targets soluble oligomeric peptides and insoluble b-amyloid fibrils with absent binding to monomeric soluble Ab. In transgenic mice with brain b-amyloid pathology, aducanumab diffused across the blood-brain-barrier, accumulated on both diffuse and compact parenchymal Ab deposits, and dose-dependently reduced brain b-amyloid load without affecting cerebrovascular amyloid deposits. In a Phase 1b study in patients with prodromal or mild Alzheimer’s disease aducanumab demonstrated an acceptable safety profile and produced a dose- and time-dependent reduction of amyloid plaque in the brain and a dose-dependent effect of slowing clinical decline. Aducanumab is currently being investigated in two Phase 3 trials in patients with early Alzheimer’s disease. Other such human antibodies developed with the same platform with favorable binding and biological activities are in early clinical or progressed preclinical development as candidate therapeutics for a-synucleinopathies, tauopathies and amyotrophic lateral sclerosis. Keywords. Aggregation, Alzheimer therapy, Amyloid beta, Antibodies, Immunotherapy
AMYLOID PET IMAGING: PRIME 1B STUDY Jeff Sevigny, Joyce Suhy, Ping Chiao, Tianle Chen, Gregory Klein, Derk Purcell, Joonmi Oh, Ajay Verma, Mehul Sampat, Jerome Barakos. N/A, N/A. E-mail: [email protected] Amyloid PET imaging is being investigated as a screening tool to identify amyloid-positive patients as an enrichment strategy for Alzheimer’s disease (AD) clinical trial enrollment. In a multicenter, Phase 1b trial, patients meeting clinical criteria for prodromal or mild AD underwent florbetapir PET scanning at screening. PET, MRI, and co-registered PET/MRI scans were reviewed by 2 independent readers and binary visual readings tabulated. Semi-quantitative values of cortical to whole cerebellar standard uptake value ratios were computed (threshold 1.10). Of 278 patients with an evaluable PET scan, 170 (61%) and 185 (67%) were amyloid-positive by visual reading and quantitative analysis, respectively; 39% were excluded from the study due to an amyloid-negative scan based on visual readings. More ApoE ε4 carriers than non-carriers were amyloid-positive (80% vs 43%). Comparison of visual readings with quantitative results identified 21 discordant cases (92% agreement). Inter- and intra-reader agreements from visual readings were 98% and 100%, respectively. Amyloid PET imaging is an effective and feasible screening tool for enrollment of amyloid-positive patients with early stages of AD into clinical trials.
Keywords. Amyloid, Axonal transport, Ab oligomers, BACE1, Dystrophic neurite, Microtubule
Keywords. Amyloid-PET, PET, Imaging
HUMAN-DERIVED MONOCLONAL ANTIBODIES FOR ALZHEIMER’S DISEASE AND RELATED PROTEINOPATHIES
LANDSCAPE OF ANTIBODY IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE
Jan Grimm1, Thierry Bussiere2, Paul Weinreb2, Marcel Maier1, Robert Dunstan2, Fang Qian2, Mahin Arastu2, Sowmya Chollate2, Melanie Brennan2, Omar Quintero-Monzon2, Robert Scannevin2, H. Arnold2, Thomas Engber2, Kenneth Rhodes2, Christoph Hock3, Alfred Sandrock2, Roger Nitsch4.
Christoph Hock1, Jan Grimm2, Jeff Sevigny2, Roger Nitsch3, Alfred Sandrock2. 1 University of Zurich, Zurich, Switzerland; 2 N/A, N/A; 3 University of Zurich, Schlieren, Switzerland. E-mail: [email protected]