Oncotarget. 2016 Jun 28;7(26):38999-39016. doi: 10.18632/oncotarget.9175.
Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities.
Pistollato F1, Ohayon EL2, Lam A1,2, Langley GR3, Novak TJ4, Pamies D5, Perry G6, Trushina E7, Williams RS8, Roher AE9,10, Hartung T5, Harnad S11, Barnard N1, Morris MC12, Lai MC1, Merkley R1, Chandrasekera PC1.
Much of Alzheimer disease (AD) research has been traditionally based on the use of animals, which have been extensively applied in an effort to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches. However, decades of such research have not effectively translated into substantial therapeutic success for human patients. Here we critically discuss these issues in order to determine how existing human-based methods can be applied to study AD pathology and develop novel therapeutics. These methods, which include patient-derived cells, computational analysis and models, together with large-scale epidemiological studies represent novel and exciting tools to enhance and forward AD research. In particular, these methods are helping advance AD research by contributing multifactorial and multidimensional perspectives, especially considering the crucial role played by lifestyle risk factors in the determination of AD risk. In addition to research techniques, we also consider related pitfalls and flaws in the current research funding system. Conversely, we identify encouraging new trends in research and government policy. In light of these new research directions, we provide recommendations regarding prioritization of research funding. The goal of this document is to stimulate scientific and public discussion on the need to explore new avenues in AD research, considering outcome and ethics as core principles to reliably judge traditional research efforts and eventually undertake new research strategies.
Alzheimer disease; Gerotarget; animal models; computational models; human methods; induced pluripotent stem cells
PMID: 27229915 DOI: 10.18632/oncotarget.9175
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Am J Neurodegener Dis. 2016 Aug 26;5(4):158-170. eCollection 2016.
Chemical and neuropathological analyses of an Alzheimer’s disease patient treated with solanezumab.
Roher AE1, Maarouf CL2, Kokjohn TA3, Belden C4, Serrano G2, Sabbagh MS5, Beach TG2.
Based on the amyloid cascade hypothesis of Alzheimer’s disease (AD) pathogenesis, a series of clinical trials involving immunotherapies have been undertaken including infusion with the IgG1 monoclonal anti-Aβ antibody solanezumab directed against the middle of the soluble Aβ peptide. In this report, we give an account of the clinical history, psychometric testing, gross and microscopic neuropathology as well as immunochemical quantitation of soluble and insoluble Aβ peptides and other proteins of interest related to AD pathophysiology in a patient treated with solanezumab.
MATERIALS AND METHODS:
The solanezumab-treated AD case (SOLA-AD) was compared to non-demented control (NDC, n = 5) and non-immunized AD (NI-AD, n = 5) subjects. Brain sections were stained with H&E, Thioflavine-S, Campbell-Switzer and Gallyas methods. ELISA and Western blots were used for quantification of proteins of interest.
The SOLA-AD subject’s neuropathology and biochemistry differed sharply from the NDC and NI-AD groups. The SOLA-AD case had copious numbers of amyloid laden blood vessels in all areas of the cerebral cortex, from leptomeningeal perforating arteries to arteriolar deposits which attained the cerebral amyloid angiopathy (CAA) maximum score of 12. In contrast, the maximum CAA for the NI-AD cases averaged a total of 3.6, while the NDC cases only reached 0.75. The SOLA-AD subject had 4.4-fold more soluble Aβ40 and 5.6-fold more insoluble Aβ40 in the frontal lobe compared to NI-AD cases. In the temporal lobe of the SOLA-AD case, the soluble Aβ40 was 80-fold increased, and the insoluble Aβ40 was 13-fold more abundant compared to the non-immunized AD cases. Both soluble and insoluble Aβ42 levels were not dramatically different between the SOLA-AD and NI-AD cohort.
Solanezumab immunotherapy provided no apparent relief in the clinical evolution of dementia in this particular AD patient, since there was a continuous cognitive deterioration and full expression of amyloid deposition and neuropathology.
Alzheimer’s disease; amyloid precursor protein; amyloid-beta; cerebral amyloid angiopathy; immunotherapy; solanezumab
PMID: 27725918 PMCID: PMC5043095
Alzheimers Res Ther. 2016 Jun 23;8(1):24. doi: 10.1186/s13195-016-0193-y.
Long-term safety and tolerability of bapineuzumab in patients with Alzheimer’s disease in two phase 3 extension studies.
Ivanoiu A1, Pariente J2, Booth K3, Lobello K3, Luscan G4, Hua L3, Lucas P4, Styren S5, Yang L3, Li D3, Black RS3, Brashear HR6, McRae T7.
Immunotherapy with monoclonal antibodies that target amyloid beta has been under investigation as a treatment for patients with Alzheimer’s disease (AD). The 3000 and 3001 phase 3 clinical studies of intravenous bapineuzumab assessed safety and efficacy in patients with mild to moderate AD recruited in over 26 countries. This article describes the long-term safety and tolerability of bapineuzumab in the extension studies for these two protocols.
The long-term safety and tolerability of intravenous-administered bapineuzumab in patients with AD was evaluated in apolipoprotein E ε4 allele noncarriers (Study 3002, extension of Study 3000) and apolipoprotein E ε4 allele carriers (Study 3003, extension of Study 3001). Those receiving bapineuzumab in the parent study were continued at the same dose; if receiving placebo, patients began bapineuzumab. Bapineuzumab doses were 0.5 mg/kg in both studies and also 1.0 mg/kg in the noncarrier study. Clinical efficacy of bapineuzumab was also assessed in exploratory analyses.
Because of lack of efficacy in two other phase 3 trials, the parent protocols were stopped early. As a result, Studies 3002 and 3003 were also terminated. In total, 492 and 202 patients were enrolled in Studies 3003 and 3002, respectively. In apolipoprotein E ε4 carriers (Study 3003), treatment-emergent adverse events occurred in 70.7% of the patients who originally received placebo and 66.9% of those who originally received bapineuzumab. In noncarriers, treatment-emergent adverse events occurred in 82.1% and 67.6% of patients who received placebo + bapineuzumab 0.5 mg/kg and placebo + bapineuzumab 1.0 mg/kg, respectively, and in 72.7% and 64.3% of those who received bapineuzumab + bapineuzumab 0.5 mg/kg and 1.0 mg/kg, respectively. Amyloid-related imaging abnormalities with edema or effusions were the main bapineuzumab-associated adverse events in both studies, occurring in approximately 11% of placebo + bapineuzumab and 4% of bapineuzumab + bapineuzumab groups overall. Exploratory analyses of clinical efficacy were not significantly different between groups in either study.
In these phase 3 extension studies, intravenous bapineuzumab administered for up to approximately 3 years showed no unexpected safety signals and a safety profile consistent with previous bapineuzumab trials.
Noncarriers (Study 3002): ClinicalTrials.gov NCT00996918 . Registered 14 October 2009. Carriers (Study 3003): ClinicalTrials.gov NCT00998764 . Registered 16 October 2009.
Alzheimer’s disease; Amyloid beta; Amyloid-related imaging abnormalities with edema or effusions/vasogenic edema; Bapineuzumab; Immunotherapy
PMID: 27334799 PMCID: PMC4918115 DOI: 10.1186/s13195-016-0193-y
Beyond immunotherapy: new approaches for disease modifying treatments for early Alzheimer’sdisease.
Current pharmacological recommendations for the treatment of Alzheimer’s disease (AD) include the cholinesterase inhibitors and the N-methyl-D-aspartate antagonist, memantine. However, these medications only manage symptoms of AD, and do not target Aβ plaques and neurofibrillary tangles. As such, there is a need to develop effective and safe disease modifying treatments that directly target AD pathology and alter the course of AD progression. Areas covered: This review evaluates ongoing phase 2 and 3 clinical trials, as well as those completed or published over the past five years. Studies for this review were obtained from clinicaltrials.gov, alzforum.org/therapeutics, and PubMed. Keywords and search criteria included: phase 2, or 3 trials related to Alzheimer’s disease, mild cognitive impairment, amyloid-beta and tau. Immunotherapies for AD have not been included as this is beyond the scope of this review. Expert opinion: A substantial number of trials investigating disease modifying drugs in AD target amyloid-beta and tau pathology. However, many of these trials have relatively short treatment duration and do not include combined assessment of biomarkers and clinical outcomes. Future investigations are recommended to include biomarker assessments and clinical outcomes over a minimum treatment duration of 18 months in order to establish disease-modifying effects.
Alzheimer’s disease; Phase 2; amyloid-beta; disease modifying; phase 3; tau
Adv Mater. 2016 Aug;28(30):6345-52. doi: 10.1002/adma.201600554. Epub 2016 May 11.
Traceable Nanoparticle Delivery of Small Interfering RNA and Retinoic Acid with Temporally Release Ability to Control Neural Stem Cell Differentiation for Alzheimer’s Disease Therapy.
Zhang R1,2, Li Y1, Hu B1, Lu Z1,3, Zhang J2, Zhang X1.
Nanoparticles that can efficiently control the differentiation of neural stem cells (NSCs) into neurons are developed for Alzheimer’s disease (AD) therapy. The treatment with these nanoparticles results in an attenuation of neuronal loss and rescues memory deficiencies in mice. The system can also be used to monitor the transplantation site, as well as the migration of NSCs in real time. Therefore, the system is proposed to open up new avenues for AD treatment.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Alzheimer’s disease; RNA; interference; magnetic resonance imaging; nanoparticles; neural stem cells
PMID: 27168033 DOI: 10.1002/adma.201600554
Expert Opin Drug Deliv. 2016 Jul;13(7):1029-43. doi: 10.1517/17425247.2016.1162152. Epub 2016 Mar 24.
Improving drug delivery technology for treating neurodegenerative diseases.
Choonara YE1, Kumar P1, Modi G2, Pillay V1.
Neurodegenerative diseases (NDs) represent intricate challenges for efficient uptake and transport of drugs to the brain mainly due to the restrictive blood-brain barrier (BBB). NDs are characterized by the loss of neuronal subtypes as sporadic and/or familial and several mechanisms of neurodegeneration have been identified.
This review attempts to recap, organize and concisely evaluate the advanced drug delivery systems designed for treating common NDs. It highlights key research gaps and opinionates on new neurotherapies to overcome the BBB as an addition to the current treatments of countering oxidative stress, inflammation and apoptotic mechanisms.
Current treatments do not fully address the biological, drug and therapeutic factors faced. This has led to the development of vogue treatments such as nose-to-brain technologies, bio-engineered systems, fusion protein chaperones, stem cells, gene therapy, use of natural compounds, neuroprotectants and even vaccines. However, failure of these treatments is mainly due to the BBB and non-specific delivery in the brain. In order to increase neuroavailability various advanced drug delivery systems provide promising alternatives that are able to augment the treatment of Alzheimer’s disease and Parkinson’s disease. However, much work is still required in this field beyond the preclinical testing phase.
Advanced drug delivery; blood-brain barrier; gene therapy; nanotechnology; neuroavailability; neurodegenerative diseases; neuroregeneration; polymer implants; proteins; scaffolds; stem cells; vaccines
PMID: 26967508 DOI: 10.1517/17425247.2016.1162152
J Mol Neurosci. 2002 Aug-Oct;19(1-2):63-9.
Development of a new treatment for Alzheimer’s disease and Parkinson’s disease using anti-aggregatory beta-synuclein-derived peptides.
Windisch M1, Hutter-Paier B, Rockenstein E, Hashimoto M, Mallory M, Masliah E.
The synaptic protein alpha-synuclein is a major constituent of Lewy bodies (LB), pathological neuronal inclusion bodies found in Parkinson’s disease (PD), Alzheimer’s disease (AD), and other neurodegenerative disorders. Owing to data from patient brains, it was speculated that an imbalance between alpha-synuclein and beta-synuclein might be one of the reasons for formation of LBs and the consequent functional deficits. This was supported by the fact that beta-synuclein is able to prevent abnormal alpha-synuclein aggregation. Transgenic mice overexpressing alpha-synuclein display LB-like inclusions in different brain regions and motor deficits. To verify if re-establishing a normal relation between alpha-synuclein and beta-synuclein is able to prevent the pathology, bigenic mice have been created that overexpress both synucleins. Beta-synuclein decreased formation of LBs by 40% and prevented functional deficits. This is considered as preliminary in vivo proof of antiaggregatory function of beta-synuclein and its potential as therapeutic substance for treatment of neurodegenerative disorders linked with abnormal protein aggregation. Peptide libraries have been synthesized to explore the active structures of beta-synuclein. The first 15 N-terminal amino-acids turned out to be important for the antiaggregatory effect. Further smaller beta-synuclein-derived peptides have screened for antiaggregatory and neuroprotective potency in different tissue-culture systems. Preliminary data suggest some of them can be used as leads for further drug development.
PMID: 12212795 DOI: 10.1007/s12031-002-0012-8