Targeting Tau in Alzheimer's Disease and Related Disorders

Agenda

* Presentation times are subject to change.

Abstracts

Active Vaccination Strategies to Prevent and Reverse Alzheimer's Disease
Michael G. Agadjanyan, PhD, DSc, Institute for Molecular Medicine, Huntington Beach, CA; and the Institute for Memory Impairments and Neurological Disorders, UC Irvine

Following the exciting first report on a successful vaccine preventing AD progression in an animal model of AD in 1999, various vaccines targeting beta amyloid (Aβ), tau, and α-Synuclein (α-syn) have proceeded to human clinical trials with mixed results. Unfortunately, unlike the comprehensive data published on AN-1792 vaccine trials by various groups, only the limited data on immunizations of AD patients with epitope vaccines composed of the small B cell epitopes form Aβ, tau, and α-syn peptides attached to a carrier molecule are available in current scientific literature. This lack of comprehensive immunological data prevents the accurate assessment of efficacy of vaccines in AD patients. More specifically, current data suggest that to be effective the vaccine should induce therapeutically relevant concentrations of antibodies targeting appropriate pathological molecules (e.g., Aβ, tau, a-syn) in elderly people with immunesenescence. In this presentation, from the standpoint of immunologists and vaccine researchers, we will discuss the various pitfalls and misconceptions encountered on the path to the successful AD epitope vaccine: (i) better standardization of immunological efficacy measures of anti-Aβ, anti-tau, and anti-α-syn vaccines; (ii) better methods to improve vaccine immunogenicity such as more immunogenic platform/carrier; and (iii) the new adjuvants required to achieve this breakthrough. We suggest that given the roles of Aβ, tau, and α-syn molecules on AD pathology and progression of disease, anti-Aβ active vaccination may be more effective in the very early stage of a disease including prodromal AD, while anti-tau and anti-α-syn immunotherapies or their combinations to be most effective in the later stages of AD.
 
Coauthor: Anahit Ghochikyan, Institute for Molecular Medicine, Huntington Beach, California.

Tau's Anatomical Footprints and Biochemical Signatures
Bernardino Ghetti, MD, Indiana University School of Medicine

Intracellular filamentous Tau inclusions accumulate in several human sporadic and inherited neurodegenerative diseases. They may occur also in some postinfectious and post-traumatic syndromes. Involved are neurons and glia, in different combinations, according to disease entity. Six Tau isoforms are expressed in adult human brain. They are produced by alternative mRNA splicing of transcripts from MAPT, the Tau gene, and differ by the presence or absence of inserts of 29 or 58 amino acids in the amino-terminal half, and the inclusion or not, of the 31 amino-acid repeat encoded by exon 10 in the carboxy-terminal half. Inclusion of exon 10 results in the production of three Tau isoforms with four repeats each (4R), and its exclusion in three isoforms with three repeats each (3R). Tau pathology occurs either as a primary event or concomitantly with a cerebral amyloidosis. Filamentous Tau differs according to disease entity and may be composed by any of the following: 3R, 4R, or 3R&4R isoforms. When Tau pathology represents the primary event, the Tau anatomical footprint varies along with the 3R, 4R, or 3R&4R signatures. Both gray and white matter may display Tau deposits in the presence of 3R or 4R signatures. The white matter pathology is severe in association with the 4R Tau signature, but not in association with the 3R&4R signature. When Tau pathology occurs concomitantly with amyloidosis, as in Alzheimer disease and in some prion diseases, the Tau signature is 3R&4R, and the anatomical footprint of Tau may be determined by the amyloid's footprint.

Mechanisms of Tau Immunotherapies
Einar M. Sigurdsson, PhD, New York University School of Medicine

The field of tau immunotherapies has advanced from proof-of-concept studies (Sigurdsson EM, R01AG020197, 2001; Asuni, AA et al, J Neurosci 2007) to clinical trials by several groups. Clearing pathological tau may be more effective in the later stages of Alzheimer's disease than removing amyloid-β, because tau pathology correlates better with cognitive impairment than amyloid-β burden. Even though clinical trials are ongoing, the mechanisms involved are not well defined. Numerous tau epitopes have been targeted with vaccines/antibodies for clearance in various models. Interestingly, most but not all approaches are effective, even when targeting the same epitope region, and higher affinity does not necessarily translate to better efficacy. Importantly as well, some antibodies appear to work primarily extracellularly whereas others can also bind to and clear/neutralize tau intracellularly. Because most of pathological tau is found within neurons, such broadly acting antibodies are likely to be more efficacious than those that can only bind to tau in the interstitial fluid. Furthermore, it is well known that antibody humanization alters its properties, and the preclinical findings to date in the tau field suggest that such engineering may substantially affect its biodistribution and efficacy. Therefore, those antibodies need to be examined carefully prior to clinical trials. These therapeutic studies have also sparked development of antibody derivatives as imaging probes, which should be more specific than the β-sheet dye compounds that are in clinical trials, and may then allow tailoring the immunotherapy to the most prevalent pathological tau epitopes in each individual.

What Tau Immunization Is Likely to Bring
Khalid Iqbal, PhD, New York State Institute for Basic Research in Developmental Disabilities

Alzheimer's disease (AD) is a slow progressive multifactorial disorder in which neurodegeneration is associated with neurofibrillary tangles of abnormally hyperphosphorylated tau (ptau), and Abeta core-neuritic (senile) plaques. Hippocampus is most affected with tau pathology and neurodegeneration in AD. In human brain tau is expressed in six alternatively spliced isoforms. In AD all six isoforms of tau are abnormally hyperphosphorylated. Tau pathology in the absence of Abeta pathology is a hallmark of a family of neurodegenerative disorders, called tauopathies. Without exception tau pathology is made up of hyperphosphorylated protein. Thus, it is reasonable to expect that inhibition of tau pathology by immunotherapy can inhibit neurodegeneration and rescue cognitive impairment. Given the involvement of six isoforms there are multiple possible patterns of tau hyperphosphorylation. Unlike normal tau which binds to microtubule protein subunit tubulin and promotes its assembly and stabilizes the microtubule network, the ptau instead binds to normal tau and templates it in a prion-like fashion into tau oligomers and filaments. We took advantage of this finding and carried out immunization with tau antibodies targeting the amino-terminal domains of tau. We found that with this strategy we can rescue not only tau but also Abeta pathology and cognitive impairment in 3×Tg-AD mouse model of AD. Furthermore, we found that the immunotherapy can also prevent the spread of AD-ptau induced pathology in tau transgenic mice. Thus, immunization targeting the amino-terminal domain of tau has the potential to lead to an effective treatment for AD and related tauopathies.

Receptor Mediated Prion-like Propagation of PH-Tau
Viktoriya Morozova, BS, Center for Developmental Neuroscience, College of Staten Island, CUNY

Alzheimer disease starts in hippocampus and progresses in well-defined pattern, a mechanism of cellular transmission is suspected. It has been shown that hyperphosphorylation of tau at Ser199, Thr212, Thr231 and Ser262 (PH-Tau) is sufficient to induce a tau pathological conformation, a structural change similar to that found in Alzheimer's. To investigate if tau can be an agent responsible for disease transmission we used two different strategies: 1) addition of the purified recombinant tau and/or PH-Tau to a cell culture medium; and 2) co-culture cells transfected with RFP-tau or GFP-PH-Tau. When recombinant protein was added to the media, we observed that both tau and PH-Tau are readily incorporated into HEK cells. The same results were found in primary neuronal culture. Additionally, we found that pretreatment of cells and primary neurons with the broad muscarinic receptor antagonist Atropine led to a great reduction of extracellular tau uptake. During co-culture, we observed that GFP-PH-Tau but no RFP-tau was released from the cells and was uptaken by neighboring cells, disrupting their cytoskeleton. These experiments suggest that PH-tau can be secreted from cells and transferred to normal cell transmitting the disease in a "prion-like" fashion through muscarinic receptors which may mediate the endocytotic mechanism.
 
Coauthor: Alejandra del C. Alonso, Center for Developmental Neuroscience, College of Staten Island, CUNY.

Transcranial Two-Photon Imaging of Tau Antibodies and Tau Aggregates in the Brains of Live Transgenic Tauopathy Mice
Qian Wu, PhD, New York University School of Medicine

Tau immunotherapies are a promising approach for Alzheimer's disease and related tauopathies. Our group published the first reports showing the effectiveness of active and passive tau immunizations in mouse models. These findings have been confirmed and extended by several groups and clinical trials have already been initiated. However, the mechanisms of antibody-mediated clearance of tau aggregates are relatively unclear, although work by us and others has clarified to some extent in culture models various pathways that may be involved. Two monoclonal antibodies (mAbs) that we have generated against the P-Ser396, 404 tau region, 4E6 and 6B2, have markedly different properties. 4E6 is more effective in various culture, ex vivo and in vivo models in preventing/reducing tau pathology and associated cognitive impairments, whereas 6B2 or rather its smaller derivatives may be better suited as a diagnostic imaging marker. Here, using in vivo two-photon imaging, we investigated the dynamics of brain uptake and clearance of fluorescently tagged 4E6 and 6B2 in live transgenic tauopathy mice. Our preliminary two-photon findings show neuronal uptake and colocalization of tau mAbs and a tau aggregate imaging dye 1-fluoro-2,5-bis (3-carboxy-4-hydroxystyryl) benzene (FSB) within the brain after intravenous injection. Based on clearance of the FSB signal, 4E6 is more efficacious in clearing tau pathology than 6B2, which fits our published findings (Congdon et al., Mol Neurodegener, 2016).This type of approach provides valuable insight into the dynamics of uptake and clearance of mAbs as well as their pathological targets in live animals, and may clarify their mechanism of action.
 
Coauthors: Yan Lin, Jiaping Gu, and Einar M. Sigurdsson, New York University School of Medicine.

Fluid Biomarkers for Tau Pathology in Alzheimer's Disease
Henrik Zetterberg, MD, PhD, University of Gothenburg, Mölndal, Sweden; Sahlgrenska University Hospital, Mölndal, Sweden; and UCL Institute of Neurology, Queen Square, London

Tau is a microtubule-binding protein that is important for the stability of neuronal axons. It is normally expressed within neurons and is also secreted into the brain interstitial fluid that communicates freely with cerebrospinal fluid (CSF) and, in a more restricted manner, blood via the glymphatic clearance system of the brain. In Alzheimer's disease (AD), neuroaxonal degeneration results in increased release of tau from neurons. Further, tau may be truncated and phosphorylated, which leads to aggregation of tau in neurofibrillary tangles of the proximal axoplasm. Neuroaxonal degeneration and tangle formation are reflected by increased concentrations of total tau (T-tau, measured using assays that detect most forms of tau) and phospho-tau (P-tau, measured using assays with antibodies specific to phosphorylated forms of tau). In AD CSF, both T-tau and P-tau concentrations are increased. In stroke and other CNS disorders with neuroaxonal injury but without tangles, T-tau is selectively increased, whilst P-tau concentration often stays normal. In tauopathies (diseases with both neurodegeneration and neurofibrillary tangles) other than AD, CSF T-tau and P-tau concentrations are typically unaltered, which is a puzzling result that warrants further investigation. In the current presentation, I discuss the association of T-tau and P-tau concentrations in body fluids with neuropathological changes, imaging findings and clinical features in AD and other CNS diseases. I will also cover the latest developments in the detection of novel tau species in biofluids and how they may reflect disease onset and progression.

Mechanisms of Pathological Tau Release in Tau Transgenic Mice and AD Synaptosomes
Emanuele Sher, MD, PhD, Eli Lilly and Company, Lilly Research Centre, United Kingdom

Tau is a microtubule binding protein expressed mainly in axons and nerve terminals. Mutations in tau are known to cause different "tauopathies" while tau aggregates and tangles are a hallmark of Alzheimer's disease (AD). Tau accumulation in synapses can cause early functional deficits, while Tau "spreading" along connected neuronal populations seems to correlate with cognitive decline in AD patients.
 
Our aim is to understand if and how synapses are affected by pathological tau and how tau spreading occurs at these synaptic sites. To study the physiological status of tau containing synapses, AD brain synaptosomes were injected in Xenopus oocytes and their functional properties analysed by two-electrode voltage clamp. Synaptic transmission was studied in hippocampal slices from tg4510 mice. Biochemical studies were performed on synaptosomes purified from transgenic mice (P301S and tg4510) and human control and AD subjects. Significant functional deficits were found in AD synaptosomes micro transplanted in oocytes, Synaptic deficits were also found in hippocampal slices from the tg4510 mice. Hyper-phosphorylated and aggregated tau (sarcosyl-insoluble, AT8+ and MC1+) was found in synaptosomes from both transgenic mice and human AD brains. Super-resolution single synapse imaging analysis confirmed that pathological tau is enriched in the presynaptic compartment. Pathological tau is released in a calcium dependent manner and its release is prevented by different botulinum toxins, confirming its vesicular nature.
 
A better understanding or the mechanism(s) of tau accumulation at, and release from, synapses could lead to novel therapeutic interventions aiming at reducing tau propagation and disease progression in AD.

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