Prefilament tau species as potential targets for immunotherapy for Alzheimer disease and related disorders

doi:10.1016/j.coi.2009.05.001

Current Opinion in Immunology

Volume 21, Issue 3, June 2009, Pages 359-363

https://doi.org/10.1016/j.coi.2009.05.001 Get rights and content

Alzheimer disease (AD) is the most common neurodegenerative disorder. Currently available therapies may slow cognitive decline but do not alter underlying disease processes. Considerable effort over the last decade has been directed toward the development of vaccines for AD; these have been primarily directed against the Aβ peptide, a component of senile plaques. More recently, alternative approaches have begun to target the microtubule binding protein tau, a component of neurofibrillary tangles. Immunotherapies based upon oligomeric species of tau represent a promising new approach for AD.

Introduction

With improved survival from chronic diseases and the aging of populations in developed countries, dramatic increases in the incidence of Alzheimer disease (AD) are predicted, with dire consequences for the economic and social fabric of many nations. Hence, the development of effective disease-modifying therapies for AD is an urgent priority for research in academia and pharmaceutical companies.

AD is a complex disease with two principle hallmarks: amyloid plaques and neurofibrillary tangles (NFT) [1]. The misfolding, aggregation, and deposition of amyloid beta (Aβ) protein gives rise to amyloid plaques, whereas aggregation of tau gives rise to NFT. The Aβ peptide is generated from the cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase. Extensive efforts have targeted various forms of Aβ aggregates for AD drug development [2]; these include reduction and alteration of APP processing, prevention of Aβ misfolding and aggregation, minimizing or eliminating its neurotoxicity, and acceleration of its clearance and degradation [3, 4, 5, 6, 7, 8].

Section snippets

Immunotherapy against Aβ

Arguably the most exciting treatment approach for AD to have evolved recently is anti-Aβ immunotherapy, first introduced by Schenk et al. in 1999; promising results were described in animal models [9]. Ten years later, the excitement about the potential of anti-Aβ immunotherapy has been largely replaced by the frustration and news of terminated clinical trials due to adverse side effects [10, 11]. Despite intensive efforts over the last decade to develop a safe and effective vaccine for AD by

Tau-based immunotherapy

Given the concerns highlighted above regarding Aβ immunotherapy, some attention is warranted for the second pathological hallmark of AD, deposition of tau. Tau plays a normal function in regulating microtubules and thus axonal transport in neurons [30]. However, misfolding and aggregation of tau is toxic to cells [31]. The amyloid hypothesis [32, 33] proposes that Aβ is the sole cause of AD and that tau aggregation is one of the many downstream events triggered by Aβ aggregation and deposition.

Role of tau oligomers in AD

The aggregation of proteins such as Aβ and tau and their deposition in many forms in AD and related neurodegenerative diseases is being studied extensively [43, 51, 52]. In the last half decade, many reports have begun to challenge the assumption inherent in the amyloid hypothesis assumption that tau aggregation is downstream of Aβ [40••, 53]. The characterization of Aβ intermediate species [54, 55] and the vast number of studies investigating their role in Aβ-mediated toxicity [56] prompted

References and recommended reading

Annotated references within the last two years:

• of special interest
•• of outstanding interest

References (76)

M. Esposito et al.
Immunogenicity and therapeutic efficacy of phage-displayed beta-amyloid epitopes
Mol Immunol
(2008)
T. Wisniewski et al.
Amyloid-beta immunisation for Alzheimer's disease
Lancet Neurol
(2008)
E.B. Lee et al.
Meningoencephalitis associated with passive immunization of a transgenic murine model of Alzheimer's amyloidosis
FEBS Lett
(2005)
C.L. Weaver et al.
Conformational change as one of the earliest alterations of tau in Alzheimer's disease
Neurobiol Aging
(2000)
J. Hardy et al.
Amyloid deposition as the central event in the aetiology of Alzheimer's disease
Trends Pharmacol Sci
(1991)
S.A. Small et al.
Linking Abeta and tau in late-onset Alzheimer's disease: a dual pathway hypothesis
Neuron
(2008)
E.M. Sigurdsson
Immunotherapy targeting pathological tau protein in Alzheimer's disease and related tauopathies
J Alzheimers Dis
(2008)
A.A. Asuni et al.
Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements
J Neurosci
(2007)
M. Goedert
Tau protein and neurodegeneration
Semin Cell Dev Biol
(2004)
J.D. Harper et al.
Observation of metastable Abeta amyloid protofibrils by atomic force microscopy
Chem Biol
(1997)

D.M. Walsh et al.

A beta oligomers — a decade of discovery

J Neurochem

(2007)

A. Bretteville et al.

Tau aggregates: toxic, inert, or protective species?

J Alzheimers Dis

(2008)

D.B. Schenk et al.

A beta immunotherapy: lessons learned for potential treatment of Alzheimer's disease

Neurodegener Dis

(2005)

E. Rockenstein et al.

Transgenic animal models of neurodegenerative diseases and their application to treatment development

Adv Drug Deliv Rev

(2007)

D.J. Selkoe

Alzheimer's disease: genes, proteins, and therapy

Physiol Rev

(2001)

A. Martinez et al.

Advances in Alzheimer therapy: understanding pharmacological approaches to the disease

Curr Alzheimer Res

(2009)

M. Zimmermann et al.

Molecular rationale for the pharmacological treatment of Alzheimer's disease

Drugs Aging

(2005)

P.S. Aisen

The development of anti-amyloid therapy for Alzheimer's disease: from secretase modulators to polymerisation inhibitors

CNS Drugs

(2005)

M. Citron

Strategies for disease modification in Alzheimer's disease

Nat Rev Neurosci

(2004)

H. Allain et al.

Alzheimer's disease: the pharmacological pathway

Fundam Clin Pharmacol

(2003)

C.I. Stains et al.

Molecules that target beta-amyloid

ChemMedChem

(2007)

M.S. Wolfe

Selective amyloid-beta lowering agents

BMC Neurosci

(2008)

D. Schenk et al.

Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse

Nature

(1999)

J.K. Foster et al.

Immunization in Alzheimer's disease: naive hope or realistic clinical potential?

Mol Psychiatry

(2009)

H.L. Weiner et al.

Immunology and immunotherapy of Alzheimer's disease

Nat Rev Immunol

(2006)

M.E. Weksler

The immunotherapy of Alzheimer's disease

Immun Ageing

(2004)

D.M. Wilcock et al.

Anti-amyloid-beta immunotherapy in Alzheimer's disease: relevance of transgenic mouse studies to clinical trials

J Alzheimers Dis

(2008)

B. Vellas et al.

Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders

Curr Alzheimer Res

(2009)

E. Masliah et al.

Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease

Neurology

(2005)

D. Boche et al.

Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain

Brain

(2008)

J.A. Nicoll et al.

Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report

Nat Med

(2003)

B. Solomon

Immunological approaches for amyloid-beta clearance toward treatment for Alzheimer's disease

Rejuvenation Res

(2008)

R. Robert et al.

Engineered antibody intervention strategies for Alzheimer's disease and related dementias by targeting amyloid and toxic oligomers

Protein Eng Des Sel

(2009)

Y. Okura et al.

DNA vaccine therapy for Alzheimer's disease: present status and future direction

Rejuvenation Res

(2008)

M.M. Racke et al.

Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta

J Neurosci

(2005)

P. Lichtlen et al.

Antibody-based approaches in Alzheimer's research: safety, pharmacokinetics, metabolism, and analytical tools

J Neurochem

(2008)

D. Walker et al.

Anti-inflammatory and immune therapy for Alzheimer's disease: current status and future directions

Curr Neuropharmacol

(2007)

D. Morgan

Immunotherapy for Alzheimer's disease

J Alzheimers Dis

(2006)

Cited by (47)

Alzheimer's disease as oligomeropathy
2018, Neurochemistry International
Citation Excerpt :
No increase in ARIA-E was observed with crenezumab in a Phase I study following either a single dose (0.3–10 mg/kg IV) or multiple (four) ascending weekly doses (0.5–5 mg/kg IV) (Adolfsson et al., 2012; Godyn et al., 2016). The previous reports indicated that mature fibrils as NFT alone is insufficient for neurodegeneration and suggests that soluble aggregates of tau may be more toxic than fibrils and critical tau species in the pathogenesis of AD and taupathies (Berger et al., 2007; Brunden et al., 2008; Kayed and Jackson, 2009; Meraz-Rios et al., 2010; Spires-Jones et al., 2011; Sydow et al., 2011; Wittmann et al., 2001). Tau oligomers are neurotoxic when applied extracellularly to cultured neuronal cells (Lasagna-Reeves et al., 2010) and promoted an increase of intracellular calcium levels by the interaction of tau with muscarinic receptors (Gomez-Ramos et al., 2006, 2008).
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder and is characterized by pathological aggregates of amyloid β-protein (Aβ) and tau protein. On the basis of genetic evidence, biochemical data, and animal models, Aβ has been suggested to be responsible for the pathogenesis of AD (the amyloid hypothesis). Aβ molecules tend to aggregate to form oligomers, protofibrils, and mature fibrils. Although mature fibrils in the final stage have been thought to be the cause of AD pathogenesis, recent studies using synthetic Aβ peptides, a cell culture model, Aβ precursor protein transgenic mice models, and human samples, such as cerebrospinal fluids and postmortem brains of AD patients, suggest that pre-fibrillar forms (oligomers of Aβ) are more deleterious than are extracellular fibril forms. Based on this recent evidence showing that oligomers have a central role in the pathogenesis of AD, the term “oligomeropathy” could be used to define AD and other protein-misfolding diseases.
In this review, I discuss recent developments in the “oligomer hypothesis” including our research findings regarding the pathogenesis of AD.
Noninfectious Disease Vaccines
2017, Plotkin's Vaccines
Immunotherapeutic Approaches for Alzheimer's Disease
2015, Neuron
Citation Excerpt :
NFTs, a pathognomonic feature of AD, are intracellular inclusion bodies that consist of deposits of paired helical filaments (PHFs), which are primarily composed of hyperphosphorylated tau. Recently, there has been considerable interest in targeting phosphorylated tau for immunomodulation in AD (Boutajangout and Wisniewski, 2014; Kayed and Jackson, 2009; Noble et al., 2009; Sigurdsson, 2008; Yoshiyama et al., 2013). Some work has shown that tau pathology precedes formation of amyloid plaques, appearing first in the locus coeruleus and then spreading to other brain stem nuclei and the entorhinal cortex (Braak and Del Tredici, 2011; Elobeid et al., 2012; Jack et al., 2013).
Alzheimer’s disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. It is characterized by an imbalance between production and clearance of amyloid β (Aβ) and tau proteins. Oligomeric forms of Aβ and tau are believed to be the most toxic. Dramatic results from AD animal models showed great promise for active and passive immune therapies targeting Aβ. However, there is very limited evidence in human studies of the clinical benefits from these approaches. Immunotherapies targeting only tau pathology have had some success but are limited so far to mouse models. The majority of current methods is based on immunological targeting of a self-protein; hence, benefits need to be balanced against risks of stimulating excessive autoimmune toxic inflammation. For greater efficacy the next generation of vaccines needs to focus more on concurrently targeting all the intermediate toxic conformers of oligomeric Aβ and tau species.
Immunotherapy for Alzheimer's disease
2014, Biochemical Pharmacology
Citation Excerpt :
NFTs are intraneuronal inclusion bodies that consist of an accumulation of paired helical filaments (PHFs), which biochemically are mainly composed of abnormally phosphorylated tau. Recently there is increasing focus on phosphorylated tau as an immunotherapeutic target [94–98]. Although most thinking in the field suggests that tau pathology is downstream from Aβ deposition [2], some studies have indicated that tau pathology begins to deposit prior to amyloid plaques in the locus ceruleus and from there spreads to other brainstem nuclei and the entorhinal cortex [99,100].
Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which serve as neuropathological markers of the disease. In addition the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat AD. Among the more exciting and advanced of these approaches is vaccination. Active and passive Immunotherapy targeting only Aβ has been successful in many AD model animal trials; however, the more limited human data has shown much less benefit so far, with encephalitis occurring in a minority of patients treated with active immunization and vasogenic edema or amyloid-related imaging abnormalities (ARIA) being a complication in some passive immunization trials. Therapeutic intervention targeting only tau has been tested only in mouse models; and no approaches targeting both pathologies concurrently has been attempted, until very recently. The immune approaches tried so far were targeting a self-protein, albeit in an abnormal conformation; however, effective enhanced clearance of the disease associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation. The design of future more effective immunomodulatory approaches will need to target all aspects of AD pathology, as well as specifically targeting pathological oligomeric conformers, without the use of any self-antigen.
New perspectives on the role of tau in Alzheimer's disease. Implications for therapy
2014, Biochemical Pharmacology
Citation Excerpt :
Mounting evidence indicates that some soluble, oligomeric (pre-filament, immature filaments) tau species, rather than the tangles, are indeed the pathogenic ones [115–117], reminiscent of what has happened in recent years in the amyloid field regarding plaques and intermediate Aβ oligomers, [118]. The demonstration of a link between tau oligomers and brain pathology in animal models (reviewed in [119]) highlights the importance of precisely identifying the tau species to be targeted by immunotherapy. Another critical point is the mechanism by which immunotherapy clear tau from the brain.
Alzheimer's disease (AD) and related dementias constitute a major public health issue due to an increasingly aged population as a consequence of generally improved medical care and demographic changes. Current drug treatment of AD, the most prevalent dementia, with cholinesterase inhibitors or NMDA antagonists have demonstrated very modest, symptomatic efficacy, leaving an unmet medical need for new, more effective therapies. While drug development efforts in the last two decades have primarily focused on the amyloid cascade hypothesis, so far with disappointing results, tau-based strategies have received little attention until recently despite that the presence of extensive tau pathology is central to the disease. The discovery of mutations within the tau gene that cause fronto-temporal dementia demonstrated that tau dysfunction, in the absence of amyloid pathology, was sufficient to cause neuronal loss and clinical dementia. Abnormal levels and hyperphosphorylation of tau protein have been reported to be the underlying cause of a group of neurodegenerative disorders collectively known as ‘tauopathies’. The detrimental consequence is the loss of affinity between this protein and the microtubules, increased production of fibrillary aggregates and the accumulation of insoluble intracellular neurofibrillary tangles. However, it has become clear in recent years that tau is not only a microtubule interacting protein, but rather has additional roles in cellular processes. This review focuses on emerging therapeutic strategies aimed at treating the underlying causes of the tau pathology in tauopathies and AD, including some novel approaches on the verge of providing new treatment paradigms within the coming years.
Noninfectious disease vaccines
2012, Vaccines: Sixth Edition

View all citing articles on Scopus

View full text

Prefilament tau species as potential targets for immunotherapy for Alzheimer disease and related disorders

Introduction

Section snippets

Immunotherapy against Aβ

Tau-based immunotherapy

Role of tau oligomers in AD

References and recommended reading

Mol Immunol

Lancet Neurol

FEBS Lett

Neurobiol Aging

Trends Pharmacol Sci

Neuron

J Alzheimers Dis

J Neurosci

Semin Cell Dev Biol

Chem Biol

J Neurochem

J Alzheimers Dis

Neurodegener Dis

Adv Drug Deliv Rev

Alzheimer's disease: genes, proteins, and therapy

Physiol Rev

Advances in Alzheimer therapy: understanding pharmacological approaches to the disease

Curr Alzheimer Res

Molecular rationale for the pharmacological treatment of Alzheimer's disease

Drugs Aging

The development of anti-amyloid therapy for Alzheimer's disease: from secretase modulators to polymerisation inhibitors

CNS Drugs

Strategies for disease modification in Alzheimer's disease

Nat Rev Neurosci

Alzheimer's disease: the pharmacological pathway

Fundam Clin Pharmacol

Molecules that target beta-amyloid

ChemMedChem

Selective amyloid-beta lowering agents

BMC Neurosci

Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse

Nature

Immunization in Alzheimer's disease: naive hope or realistic clinical potential?

Mol Psychiatry

Immunology and immunotherapy of Alzheimer's disease

Nat Rev Immunol

The immunotherapy of Alzheimer's disease

Immun Ageing

Anti-amyloid-beta immunotherapy in Alzheimer's disease: relevance of transgenic mouse studies to clinical trials

J Alzheimers Dis

Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders

Curr Alzheimer Res

Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease

Neurology

Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain

Brain

Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report

Nat Med

Immunological approaches for amyloid-beta clearance toward treatment for Alzheimer's disease

Rejuvenation Res

Engineered antibody intervention strategies for Alzheimer's disease and related dementias by targeting amyloid and toxic oligomers

Protein Eng Des Sel

DNA vaccine therapy for Alzheimer's disease: present status and future direction

Rejuvenation Res

Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta

J Neurosci

Antibody-based approaches in Alzheimer's research: safety, pharmacokinetics, metabolism, and analytical tools

J Neurochem

Anti-inflammatory and immune therapy for Alzheimer's disease: current status and future directions

Curr Neuropharmacol

Immunotherapy for Alzheimer's disease

J Alzheimers Dis