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Abeta oligomer selective immunotherapy based on beta amyloid dysfunction hypothesis
- 1. Amyloid Beta Dysfunction Hypothesis Heinz Hillen, January 2019
- 2. The classical beta amyloid cascade hypothesis Basics and issues • Beta amyloid protein is accumulating in the brain and finally produces deposits as amyloid plaques • Amyloid aggregates are toxic and expected to initiate the neurophathological chain of events mediated through receptors and also possibly via Tau • Ultimately these events are leading to AD ➢Major weakness: • The current amyloid cascade hypothesis basically ignores the physiological role of Aβ monomer in synaptic processes 2
- 3. The classical beta amyloid cascade hypothesis: Lowering beta amyloid production failed in the clinic ➢Lowering Amyloid beta production levels via Gamma- or Beta-Secretase inhibitors or immunotherapy will reduce amyloid deposits ➢ This approach has led to many disappointments in clinical trials: − Gamma secretase inhibitors failed and produced cognitive side effects − Beta secretase inhibitors have not produced a significant clinical effect so far; (pre)clinical evidence for synaptic impairment at higher doses − Pan Abeta antibodies have shown poor efficacy, if at all 3
- 4. 4 The confusion around “Amyloid beta, Aβ“ Three very different types of proteins sharing the same name Aβ Amyloid beta (x-y) Aβ isoform Physiologica l Aβ monomer Misfolded Aβ (Soluble Oligomers) Fibrillar Aβ 3D structure Metastable unknown* Core structure by NMR X-ray structure Varieties 1-40,1-42 x-40,42**, AA-Modifications (e.g. pGlu), Lipid complexes and combinations, but shared conserved 20-30 epitope 1-40,1-42 • Categorizing between „the good Aβ“ , „the early neurotoxic Aβ (soluble oligomers)“ and „the fibril type Aβ (plaques)“ * unstable outside CSF, Plasma ** x =1-4 Early pathology fast Protofibril/fibril pathology, slow ?
- 5. Revising the amyloid cascade hypothesis: Aβ monomer is essential for synaptic processes 5 Item Key data Paper Synaptic processes Endogenously released Aβ peptides regulate synaptic transfer at single presynaptic terminals and synaptic connections in rodent hippocampal cultures and slices E. Abramov, Nature Neuroscience 2009 Synaptic activity Inhibiting neuronal activity by TTX (EEG) decreases ISF Aβ levels Ciritto et al., Neuron 2005 Procognitive effects • Low doses of monomeric Abeta (administered ICV) improves cognitive behavior in non TG mice • Anti monomer Aβ antibody impairs cognitive behavior in non TG mice • Aβ monomer is essential for LTP • Impaired learning by anti sense Aβ Morey et al., Journal of Alzheimer’s Disease 2010 APP KO mice • Impaired LTP • Poor performance in spatial memory tasks • Reduced synapses Dawson GR, et al Neuroscience 1999, Seebrook et al., Neuropharmacology 1999 PS1 deficient mice • Reduced Abeta levels • Impaired LTP Morton RA, Neurosci Lett ,, 2002
- 6. Revising the amyloid cascade hypothesis: The Beta Amyloid Dysfunction (BAD) hypothesis in AD • Physiological Beta amyloid is a key molecule in synaptic transmission. Its biogenesis and turnover is an essential physiological process conserved in neurons of vertebrates • Maintaining sufficient synaptic Aβ levels is essential and extremely complex: Aβ is a metastable peptide produced at high rates and high turnover in neurons • Aβ pathophysiology is assumed to start, when the high energy dependent Aβ formation and metabolism process is disturbed. • Impairment in the Aβ turnover process creates: 1. early misfolded neuropathogenic species and 2. reduced synaptic physiological Aβ levels: → Beta Amyloid Dysfunction (BAD) Hypothesis 6
- 7. The Beta Amyloid Dysfunction Hypothesis 1. The Beta Amyloid physiological process 7 Aa a Aa A Synaptic transmission Synaptic processes in neurons Neuronal function 1. Aβ monomer is maintained at synaptic processes in a proper concentration and folding BACE Aβ pools in CSF and Plasma are gold standards for clean Aβ monomer
- 8. The Beta Amyloid Dysfunction Hypothesis (BAD) 2. The Beta Amyloid patho-physiological process 8 Aa a Aa A Dysregulation of Aβ pathway 2. Disease process through Aβ misfolding: early misfolded Aβ species emerge and synaptic levels of physiological Aβ are reduced Synaptic deficits via 1. Aβ oligomers↑ 2. Aβ monomer↓ BACE Neuronal dysfunction via Aβ oligomer effects on promiscuous receptors
- 9. The Beta Amyloid Dysfunction Hypothesis (BAD) 3. Compensation worsens pathology: a vicious circle 9 Aa a Aa A BACE 3. Compensatory mechanisms in early Aβ pathology : APP processing enhanced to substitute synaptic Aβ monomer deficits compensatory APP processing via upregulation of BACE to restore Aβ monomer mediated synaptic function Dysregulation of Aβ pathway Synaptic deficits via 1. Aβ oligomers↑ 2. Aβ monomer↓ Neuronal dysfunction via Aβ oligomer effects on promiscuous receptors
- 10. The Beta Amyloid Dysfunction Hypothesis (BAD) Immunotherapy reverses Aβ dysregulation 10 Aa a Aa A BACE Neuronal dysfunction via Aβ oligomer effects on promiscuous receptors Synaptic deficits via 1. Aβ oligomers↓ 2. Aβ monomer↑ Aβ pathway normalized Removing Aβ misfolded species in neurons by highly conformer specific antibodies should reinstate normal Aβ processing and rescue neurons Y complex eliminated X compensatory APP processing via upregulation of BACE to restore Aβ monomer mediated synaptic function X
- 11. The pathology starts inside the neuron Intraneuronal Aβ1-42 accumulation 11 Findings Tools Paper Aβ 4-42 early intraneural accumulation and rescue of toxicity NT4X-167, a novel monoclonal antibody demonstrated intraneural staining; 5XFAD mice Antonios , G.et al. Acta Neuropathologica Communications 2013 Genetic and pharmacological evidence of intraneuronal Aβ accumulation in APP transgenic mice BACE-1 deficient APP transgenic mice: neither Aβ production nor intraneuronal immunostaining. O.Philipson et al. FEBS Letters 2009 Both intraneuronal Aβ accumulation and extracellular Aβ deposition was demonstrated MOAB-2 antibody detects N- terminal Aβ; 5XFAD mice Youmans, KL et al.; Mol Neurodegener., 2012 Human APOE genotype affects Intraneuronal Aβ1-42 Accumulation Lentiviral Gene Transfer Model W.Zhao et al. Human Molecular Genetics, 2014
- 12. The Beta amyloid cascade versus BAD hypothesis - Major differences and therapeutic implications (I) 12 Item Beta amyloid cascade Hypothesis Beta amyloid dysfunction (BAD) Hypothesis Physiological Aβ monomer precursor for aggregated Aβ to be preserved at sufficient concentrations in synaptic processes Pathophysiology amyloid deposits (protofibrils, fibrils) misfolded species formed in neurons Reduced Aβ CSF levels in AD difficult to explain explained by interdependent and opposite proteins: Aβ monomer vs. Aβ oligomers APP KO mice mice are viable age dependent learning deficits indicate that Aβ is essential in synaptic processes Genetic AD link in fAD not all PS mutations explained by Aβ overproduction all PS mutations interfere with maintainance of regular physiological Aβ monomer Aβ lowering strategy? Yes BACE and Gamma-Secretase inhibitors lower aggregation propensity No 1. risk of cognitive deficits through lowering physiological Aβ monomer at synaptic sites 2. Antibody consumption by excess
- 13. The Beta amyloid cascade versus BAD hypothesis - Major differences and therapeutic implications (II) 13 Item Beta amyloid cascade Hypothesis Beta amyloid dysfunction (BAD) Hypothesis Gamma secretase inhibitors + failure explained by Notch or AICD mediated side effects - (+) for modulators inferior with role of physiological Aβ synaptic function; Aβ modulators do not change overall β concentration BACE Inhibitors + impaired synaptic plasticity and cognition in adult rats (high dose) - inferior with role of physiological Aβ synaptic function Pan Aβ immunotherapy + dose limiting side effects (e.g ARIA) - 1. inferior with role of physiological Aβ synaptic function 2. consumption of Mabs in plasma avoid CNS exposure Early misfolded Aβ oligomer specific immunotherapy + a recent antibody solved one of two problems: monomer selectivity but not plaque dissolution (ARIA) + neutralizing low fraction of pathogenic misfolded Aβ species generated during impaired neuronal Aβ processing
- 14. The Beta Amyloid Dysfunction (BAD) hypothesis in AD - Immunotherapy via early misfolded Aβ specific Ab´s • Aβ deposits in parenchyma and plaques are not the primary target for the treatment of Aβ pathology in AD • An effective immunotherapy treatment requires presence of conformer selective antibodies which remove misfolded species thereby restoring physiological Aβ function 14