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156


Tau-targeting therapies for Alzheimer disease: current status and future directions

Congdon, Erin E; Ji, Changyi; Tetlow, Amber M; Jiang, Yixiang; Sigurdsson, Einar M
Alzheimer disease (AD) is the most common cause of dementia in older individuals. AD is characterized pathologically by amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain, with associated loss of synapses and neurons, which eventually results in dementia. Many of the early attempts to develop treatments for AD focused on Aβ, but a lack of efficacy of these treatments in terms of slowing disease progression led to a change of strategy towards targeting of tau pathology. Given that tau shows a stronger correlation with symptom severity than does Aβ, targeting of tau is more likely to be efficacious once cognitive decline begins. Anti-tau therapies initially focused on post-translational modifications, inhibition of tau aggregation and stabilization of microtubules. However, trials of many potential drugs were discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting agents in clinical trials are immunotherapies. In this Review, we provide an update on the results from the initial immunotherapy trials and an overview of new therapeutic candidates that are in clinical development, as well as considering future directions for tau-targeting therapies.
PMID: 37875627
ISSN: 1759-4766
CID: 5606262

Single-domain antibody-based noninvasive in vivo imaging of α-synuclein or tau pathology

Jiang, Yixiang; Lin, Yan; Krishnaswamy, Senthilkumar; Pan, Ruimin; Wu, Qian; Sandusky-Beltran, Leslie A; Liu, Mengyu; Kuo, Min-Hao; Kong, Xiang-Peng; Congdon, Erin E; Sigurdsson, Einar M
Intracellular deposition of α-synuclein and tau are hallmarks of synucleinopathies and tauopathies, respectively. Recently, several dye-based imaging probes with selectivity for tau aggregates have been developed, but suitable imaging biomarkers for synucleinopathies are still unavailable. Detection of both of these aggregates early in the disease process may allow for prophylactic therapies before functional impairments have manifested, highlighting the importance of developing specific imaging probes for these lesions. In contrast to the β sheet dyes, single-domain antibodies, found in camelids and a few other species, are highly specific, and their small size allows better brain entry and distribution than whole antibodies. Here, we have developed such imaging ligands via phage display libraries derived from llamas immunized with α-synuclein and tau preparations, respectively. These probes allow noninvasive and specific in vivo imaging of α-synuclein versus tau pathology in mice, with the brain signal correlating strongly with lesion burden. These small antibody derivatives have great potential for in vivo diagnosis of these diseases.
PMCID:10171817
PMID: 37163602
ISSN: 2375-2548
CID: 5476842

Development of brain-penetrable antibody radioligands for in vivo PET imaging of amyloid-β and tau

Banka, Vinay; Kelleher, Andrew; Sehlin, Dag; Hultqvist, Greta; Sigurdsson, Einar M; Syvänen, Stina; Ding, Yu-Shin
INTRODUCTION/UNASSIGNED:PET imaging. METHODS/UNASSIGNED:F]SFB in acetonitrile/0.1 M borate buffer solution (final pH ~ 8.5) with an incubation of 20 min at room temperature, followed by purification on a PD MiniTrap G-25 size exclusion gravity column. RESULTS/UNASSIGNED:F]SFB and bispecific antibodies showed a 65%-83% conversion efficiency with radiochemical purities of 95%-99% by radio-TLC. CONCLUSIONS/UNASSIGNED:PET imaging.
PMCID:10483511
PMID: 37680310
ISSN: 2673-8880
CID: 5623752

Amyloid-β targeting immunisation in aged non-human primate (Microcebus murinus).

Trouche, Stéphanie G; Boutajangout, Allal; Asuni, Ayodeji; Fontés, Pascaline; Sigurdsson, Einar M; Verdier, Jean-Michel; Mestre-Francés, Nadine
Non-human primates have an important translational value given their close phylogenetic relationship to humans. Studies in these animals remain essential for evaluating efficacy and safety of new therapeutic approaches, particularly in aging primates that display Alzheimer's disease (AD) -like pathology. With the objective to improve amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an active immunisation with an Aβ derivative, K6Aβ1-30-NH2, in old non-human primates. Thirty-two aged (4-10 year-old) mouse lemurs were enrolled in the study, and received up to four subcutaneous injections of the vaccine in alum adjuvant or adjuvant alone. Even though antibody titres to Aβ were not high, pathological examination of the mouse lemur brains showed a significant reduction in intraneuronal Aβ that was associated with reduced microgliosis, and the vaccination did not lead to microhemorrhages. Moreover, a subtle cognitive improvement was observed in the vaccinated primates, which was probably linked to Aβ clearance. This Aβ derivative vaccine appeared to be safe as a prophylactic measure based on the brain analyses and because it did not appear to have detrimental effects on the general health of these old animals.
PMID: 36592872
ISSN: 1090-2139
CID: 5403772

Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity

Congdon, Erin E; Pan, Ruimin; Jiang, Yixiang; Sandusky-Beltran, Leslie A; Dodge, Andie; Lin, Yan; Liu, Mengyu; Kuo, Min-Hao; Kong, Xiang-Peng; Sigurdsson, Einar M
BACKGROUND:Eleven tau immunoglobulin G (IgG) antibodies have entered clinical trials to treat tauopathies, including Alzheimer's disease, but it is unclear which IgG subclass/subtype has the ideal efficacy and safety profile. Only two subtypes, with or without effector function, have been examined in the clinic and not for the same tau antibody. The few preclinical studies on this topic have only compared two subtypes of one antibody each and have yielded conflicting results. METHODS:subclasses containing identical tau binding domains but differing Fc region. Unmodified sdAbs and their IgG subclasses were tested for efficacy in primary cultures and in vivo microdialysis using JNPL3 tauopathy mice. FINDINGS/RESULTS:subclasses varied greatly within and between sdAbs. For one of them, all its subtypes were non-toxic, only those with effector function cleared tau, and were more effective in vivo than unmodified sdAb. For the other sdAb, all its subtypes were toxic in tauopathy cultures but not in wild-type cells, suggesting that bivalent binding of its tau epitope stabilizes a toxic conformation of tau, with major implications for tau pathogenesis. Likewise, its subclasses were less effective than the unmodified sdAb in clearing tau in vivo. INTERPRETATION/CONCLUSIONS:These findings indicate that tau antibodies with effector function are safe and better at clearing pathological tau than effectorless antibodies, Furthermore, tau antibodies can provide a valuable insight into tau pathogenesis, and some may aggravate it. FUNDING/BACKGROUND:Funding for these studies was provided by the National Institute of Health (R01 AG032611, R01 NS077239, RF1 NS120488, R21 AG 069475, R21 AG 058282, T32AG052909), and the NYU Alzheimer's Disease Center Pilot Grant Program (via P30 AG008051).
PMCID:9475275
PMID: 36099813
ISSN: 2352-3964
CID: 5332822

Targeting tau only extracellularly is likely to be less efficacious than targeting it both intra- and extracellularly

Congdon, Erin E; Jiang, Yixiang; Sigurdsson, Einar M
Aggregation of the tau protein is thought to be responsible for the neurodegeneration and subsequent functional impairments in diseases that are collectively named tauopathies. Alzheimer's disease is the most common tauopathy, but the group consists of over 20 different diseases, many of which have tau pathology as their primary feature. The development of tau therapies has mainly focused on preventing the formation of and/or clearing these aggregates. Of these, immunotherapies that aim to either elicit endogenous tau antibodies or deliver exogenous ones are the most common approach in clinical trials. While their mechanism of action can involve several pathways, both extra- and intracellular, pharmaceutical companies have primarily focused on antibody-mediated clearance of extracellular tau. As we have pointed out over the years, this is rather surprising because it is well known that most of pathological tau protein is found intracellularly. It has been repeatedly shown by several groups over the past decades that antibodies can enter neurons and that their cellular uptake can be enhanced by various means, particularly by altering their charge. Here, we will briefly describe the potential extra- and intracellular mechanisms involved in antibody-mediated clearance of tau pathology, discuss these in the context of recent failures of some of the tau antibody trials, and finally provide a brief overview of how the intracellular efficacy of tau antibodies can potentially be further improved by certain modifications that aim to enhance tau clearance via specific intracellular degradation pathways.
PMID: 34896021
ISSN: 1096-3634
CID: 5109542

Alzheimer's disease research progress in Australia: The Alzheimer's Association International Conference Satellite Symposium in Sydney

Sexton, Claire E; Anstey, Kaarin J; Baldacci, Filippo; Barnum, C J; Barron, Anna M; Blennow, Kaj; Brodaty, Henry; Burnham, Samantha; Elahi, Fanny M; Götz, Jürgen; Jeon, Yun-Hee; Koronyo-Hamaoui, Maya; Landau, Susan M; Lautenschlager, Nicola T; Laws, Simon M; Lipnicki, Darren M; Lu, Hanzhang; Masters, Colin L; Moyle, Wendy; Nakamura, Akinori; Pasinetti, Giulio Maria; Rao, Naren; Rowe, Christopher; Sachdev, Perminder S; Schofield, Peter R; Sigurdsson, Einar M; Smith, Kate; Srikanth, Velandai; Szoeke, Cassandra; Tansey, Malú G; Whitmer, Rachel; Wilcock, Donna; Wong, Tien Y; Bain, Lisa J; Carrillo, Maria C
The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia.
PMID: 34058063
ISSN: 1552-5279
CID: 4911832

Current Status of Clinical Trials on Tau Immunotherapies

Ji, Changyi; Sigurdsson, Einar M
Tau immunotherapies have advanced from proof-of-concept studies to over a dozen clinical trials for Alzheimer's disease (AD) and other tauopathies. Mechanistic studies in animal and culture models have provided valuable insight into how these therapies may work but multiple pathways are likely involved. Different groups have emphasized the importance of intracellular vs extracellular antibody-mediated clearance of the tau protein and there is no consensus on which pool of tau should ideally be targeted. Likewise, various normal and disease-selective epitopes are being targeted, and the antibody isotypes either favor phagocytosis of the tau-antibody complex or are neutral in that aspect. Most of the clinical trials are in early stages, thus their efficacy is not yet known, but all have been without any major adverse effects and some have reported target engagement. A few have been discontinued. One in phase I, presumably because of a poor pharmacokinetic profile, and three in phase II for a lack of efficacy although this trial stage is not well powered for efficacy measures. In these phase II studies, trials with two antibodies in patients with progressive supranuclear palsy or other primary tauopathies were halted but are continuing in patients with AD, and one antibody trial was stopped in early-stage AD but is continuing in moderate AD. These three antibodies have been reported to only work extracellularly and tau is not increased in the cerebrospinal fluid of primary tauopathies, which may explain the failures of two of them. In the discontinued AD trial, there are some concerns about how much of extracellular tau contains the N-terminal epitope that is being targeted. In addition, extracellular tau is only a small part of total tau, compared to intracellular tau. Targeting only the former may not be sufficient for functional benefits. Given these outcomes, decision makers within the pharmaceutical companies who green light these trials should attempt to target tau not only extracellularly but also intracellularly to increase their chances of success. Hopefully, some of the ongoing trials will provide some functional benefits to the large number of patients with tauopathies.
PMID: 34101156
ISSN: 1179-1950
CID: 4936642

Increased neuronal activity in motor cortex reveals prominent calcium dyshomeostasis in tauopathy mice

Wu, Qian; Bai, Yang; Li, Wei; Congdon, Erin E; Liu, Wenke; Lin, Yan; Ji, Changyi; Gan, Wen-Biao; Sigurdsson, Einar M
Perturbed neuronal Ca2+ homeostasis is implicated in Alzheimer's disease, which has primarily been demonstrated in mice with amyloid-β deposits but to a lesser and more variable extent in tauopathy models. In this study, we injected AAV to express Ca2+ indicator in layer II/III motor cortex neurons and measured neuronal Ca2+ activity by two photon imaging in awake transgenic JNPL3 tauopathy and wild-type mice. Various biochemical measurements were conducted in postmortem mouse brains for mechanistic insight and a group of animals received two intravenous injections of a tau monoclonal antibody spaced by four days to test whether the Ca2+ dyshomeostasis was related to pathological tau protein. Under running conditions, we found abnormal neuronal Ca2+ activity in tauopathy mice compared to age-matched wild-type mice with higher frequency of Ca2+ transients, lower amplitude of peak Ca2+ transients and lower total Ca2+ activity in layer II/III motor cortex neurons. While at resting conditions, only Ca2+ frequency was increased. Brain levels of soluble pathological tau correlated better than insoluble tau levels with the degree of Ca2+ dysfunction in tauopathy mice. Furthermore, tau monoclonal antibody 4E6 partially rescued Ca2+ activity abnormalities in tauopathy mice after two intravenous injections and decreased soluble pathological tau protein within the brain. This correlation and antibody effects strongly suggest that the neuronal Ca2+ dyshomeostasis is causally linked to pathological tau protein. These findings also reveal more pronounced neuronal Ca2+ dysregulation in tauopathy mice than previously reported by two-photon imaging that can be partially corrected with an acute tau antibody treatment.
PMID: 33166699
ISSN: 1095-953x
CID: 4734562

Tau immunotherapies: Lessons learned, current status and future considerations

Sandusky-Beltran, L A; Sigurdsson, E M
The majority of clinical trials targeting the tau protein in Alzheimer's disease and other tauopathies are tau immunotherapies. Because tau pathology correlates better with the degree of dementia than amyloid-β lesions, targeting tau is likely to be more effective in improving cognition than clearing amyloid-β in Alzheimer's disease. However, the development of tau therapies is in many ways more complex than for amyloid-β therapies as briefly outlined in this review. Most of the trials are on humanized antibodies, which may have very different properties than the original mouse antibodies. The impact of these differences are to a large extent unknown, can be difficult to decipher, and may not always be properly considered. Furthermore, the ideal antibody properties for efficacy are not well established and can depend on several factors. However, considering the varied approaches in clinical trials, there is a general optimism that at least some of these trials may provide functional benefits to patients suffering of various tauopathies.
PMID: 32360477
ISSN: 1873-7064
CID: 4439062