Therapeutic Strategies for Tau Mediated Neurodegeneration
Therapeutic Strategies for Tau Mediated Neurodegeneration
Based on the amyloid hypothesis, controlling β-amyloid protein (Aβ) accumulation is supposed to suppress downstream pathological events, tau accumulation, neurodegeneration and cognitive decline. However, in recent clinical trials, Aβ removal or reducing Aβ production has shown limited efficacy. Moreover, while active immunisation with Aβ resulted in the clearance of Aβ, it did not prevent tau pathology or neurodegeneration. This prompts the concern that it might be too late to employ Aβ targeting therapies once tau mediated neurodegeneration has occurred. Therefore, it is timely and very important to develop tau directed therapies. The pathomechanisms of tau mediated neurodegeneration are unclear but hyperphosphorylation, oligomerisation, fibrillisation and propagation of tau pathology have been proposed as the likely pathological processes that induce loss of function or gain of toxic function of tau, causing neurodegeneration. Here we review the strategies for tau directed treatments based on recent progress in research on tau and our understanding of the pathomechanisms of tau mediated neurodegeneration.
Alzheimer's disease (AD) is the most common cause of dementia, contributing to up to 70% of dementia cases. As the global population ages, nearly 35.6 million people worldwide are estimated to be living with dementia, and the number of people with dementia is predicted to double by 2030 (65.7 million) and more than triple by 2050 (115.4 million) if effective disease modifying therapies are not developed. Current therapies for AD only provide symptomatic relief, either by temporarily improving symptoms above baseline or by delaying cognitive decline. Thus disease modifying therapies based on the pathomechanisms of AD are a central focus of AD drug discovery.
AD has two pathological hallmarks: senile plaques (SPs), consisting of β-amyloid protein (Aβ), and neurofibrillary tangles (NFTs), consisting of tau protein. Mutations in the amyloid precursor protein (APP) gene that lead to excess production or reduced clearance of Aβ in the brain, and mutations in the genes encoding protease subunits (ie, presenilin (PS) 1 and 2, involved in cleavage of APP to generate amyloidogenic Aβ peptides) induce AD in an autosomal dominant manner. Therefore, abnormal accumulation of Aβ is speculated to be the most important and disease specific pathomechanism involved in the initiation of the multiple pathological steps leading to Aβ oligomerisation, abnormal tau aggregation, synaptic dysfunction, cell death and brain shrinkage. This assumption is widely accepted as the amyloid hypothesis of AD. The results of clinicopathological studies and recent clinical studies using biomarkers, including amyloid positron emission tomography (PET), 2-[18 F]-fluoro-2-deoxy-D-glucose (FDG)-PET, CSF analysis of Aβ and tau/p-tau, and MRI support the amyloid hypothesis. Neocortical SPs appear in the preclinical phase more than 10 years earlier than neocortical NFTs, and NFT expansion accompanies cognitive decline.
This hypothesis has been further supported by a recent cross sectional analysis study looking at families with autosomal dominant AD. By using the participant's age and their parent's age at symptom onset, researchers estimated the years from expected symptom onset of AD. They could then determine the relative order and magnitude of pathophysiological changes associated with AD, although it is still uncertain whether sporadic AD has a similar pathophysiological process to inherited AD. However, other studies indicate that tau pathology appears at a younger age than SPs and most recently Braak and Del Tredici, and Elobeid et al demonstrated tau positive pathology in cases less than 30 years of age. Based on these data, they propose that tau pathology begins to deposit in the locus coeruleus and then spreads from there to other brainstem nuclei and to the entorhinal cortex (EC), perhaps by direct cell to cell transmission. This has led to an alternative hypothesis that subcortical tangle pathology before SP formation represents the earliest stages of tau pathology in sporadic AD (Figure 1). However, other interpretations cannot be excluded, such as this tau pathology is merely an insignificant alternation related to aging, or that soluble oligomeric Aβ accumulation precedes this early tau pathology.
(Enlarge Image)
Figure 1.
Chronological relationships among pathology, clinical symptoms and biomarkers. Based on biomarker studies, β-amyloid protein (Aβ) accumulation appears to start ~20 years before the onset of dementia. Amyloid positron emission tomography (PET) or a decrease in Aβ1–42 levels in CSF may indicate Aβ accumulation in the brain, even in preclinical Alzheimer's disease (AD). Neocortical tau pathology correlates closely with the timing of symptom onset. But, as discussed in the text, these findings need to be reconciled with reports by Braak and colleagues that tau pathology is seen in the brain prior to Aβ pathology, while functional MRI (fMRI) abnormalities may be the earliest biomarker to change in the preclinical phase of AD.11–14 FDG, 2-[18 F]-fluoro-2-deoxy-D-glucose; MCI, mild cognitive impairment.
Aβ biomarker (amyloid PET, Aβ1–42 in CSF) abnormalities precede synaptic dysfunction (FDG-PET) and tau biomarker (tau/p-tau in CSF) abnormalities, followed by brain structural changes (structural MRI) and, finally, cognitive decline (figure 1). However, other studies suggest that functional MRI, which indicates neuronal hyperconnectivity or hypoconnectivity, may show abnormalities before amyloid biomarkers become abnormal, thereby suggesting this may be the earliest biomarker to change in preclinical AD (figure 1). According to the amyloid cascade hypothesis, pharmacological agents that reduce brain Aβ content are supposed to act as effective drugs against AD; several different candidate drugs of this type have been developed. However, clinical trials directed at increasing the clearance or decreasing production of Aβ, which are at different stages of development, have been largely disappointing. Active immunisation with Aβ (AN1792) resulted in impressive clearance of SPs from the brain, as confirmed by pathological examination, but did not prevent progressive cognitive decline, NFT formation or neurodegeneration. Moreover, neither tarenflurbil nor semagacestat (http://files.shareholder.com/downloads/LLY/1921397628x0x395879/54b1f68f-c7b8-4c04-87d1-8c609c21f6f7/LLY_News_2010_8_17_Product.pdf), which act to decrease the production of Aβ, showed any clinical benefits. Most recently, the results on the phase III clinical trials of passive immunisations against Aβ (bapineuzumab and ?solanezumab) were announced (http://www.pfizer.com/news/press_releases/pfizer_press_release.jsp?guid=20120806006130en&source=RSS_2011&page=1; http://newsroom.lilly.com/releasedetail.cfm?releaseid=702211). None of these clinical trials proved significant efficacy of the primary endpoints, although the potential efficacy was not completely denied.
These observations have challenged the assumption that Aβ induces tau mediated neurodegeneration, and the work of Braak et al are consistent with the view that tau pathology emerges autonomously and independently from Aβ, and tau pathology may be the more proximal cause of neurodegeneration in AD. This view is supported by findings in AD mouse models: Aβ immunotherapy in 3×Tg-AD (PS1 (M146V), APP (Swe) and tau (P301L)) mice resulted in a reduction in extracellular SPs and intracellular Aβ accumulation and led to the clearance of less phosphorylated tau pathology; however, hyperphosphorylated tau aggregates were unaffected by Aβ antibody treatment. Additionally, reduction of both soluble Aβ and tau levels, but not a reduction of soluble Aβ levels alone, ameliorated cognitive decline. Therefore, Aβ targeting therapies might exert preventive effects in the preclinical or very early clinical stages of AD, but once cognitive decline appears in association with accumulations of tau pathology, then tau targeting drugs might be necessary for disease modification (Figure 1).
Abstract and Introduction
Abstract
Based on the amyloid hypothesis, controlling β-amyloid protein (Aβ) accumulation is supposed to suppress downstream pathological events, tau accumulation, neurodegeneration and cognitive decline. However, in recent clinical trials, Aβ removal or reducing Aβ production has shown limited efficacy. Moreover, while active immunisation with Aβ resulted in the clearance of Aβ, it did not prevent tau pathology or neurodegeneration. This prompts the concern that it might be too late to employ Aβ targeting therapies once tau mediated neurodegeneration has occurred. Therefore, it is timely and very important to develop tau directed therapies. The pathomechanisms of tau mediated neurodegeneration are unclear but hyperphosphorylation, oligomerisation, fibrillisation and propagation of tau pathology have been proposed as the likely pathological processes that induce loss of function or gain of toxic function of tau, causing neurodegeneration. Here we review the strategies for tau directed treatments based on recent progress in research on tau and our understanding of the pathomechanisms of tau mediated neurodegeneration.
Introduction
Alzheimer's disease (AD) is the most common cause of dementia, contributing to up to 70% of dementia cases. As the global population ages, nearly 35.6 million people worldwide are estimated to be living with dementia, and the number of people with dementia is predicted to double by 2030 (65.7 million) and more than triple by 2050 (115.4 million) if effective disease modifying therapies are not developed. Current therapies for AD only provide symptomatic relief, either by temporarily improving symptoms above baseline or by delaying cognitive decline. Thus disease modifying therapies based on the pathomechanisms of AD are a central focus of AD drug discovery.
AD has two pathological hallmarks: senile plaques (SPs), consisting of β-amyloid protein (Aβ), and neurofibrillary tangles (NFTs), consisting of tau protein. Mutations in the amyloid precursor protein (APP) gene that lead to excess production or reduced clearance of Aβ in the brain, and mutations in the genes encoding protease subunits (ie, presenilin (PS) 1 and 2, involved in cleavage of APP to generate amyloidogenic Aβ peptides) induce AD in an autosomal dominant manner. Therefore, abnormal accumulation of Aβ is speculated to be the most important and disease specific pathomechanism involved in the initiation of the multiple pathological steps leading to Aβ oligomerisation, abnormal tau aggregation, synaptic dysfunction, cell death and brain shrinkage. This assumption is widely accepted as the amyloid hypothesis of AD. The results of clinicopathological studies and recent clinical studies using biomarkers, including amyloid positron emission tomography (PET), 2-[18 F]-fluoro-2-deoxy-D-glucose (FDG)-PET, CSF analysis of Aβ and tau/p-tau, and MRI support the amyloid hypothesis. Neocortical SPs appear in the preclinical phase more than 10 years earlier than neocortical NFTs, and NFT expansion accompanies cognitive decline.
This hypothesis has been further supported by a recent cross sectional analysis study looking at families with autosomal dominant AD. By using the participant's age and their parent's age at symptom onset, researchers estimated the years from expected symptom onset of AD. They could then determine the relative order and magnitude of pathophysiological changes associated with AD, although it is still uncertain whether sporadic AD has a similar pathophysiological process to inherited AD. However, other studies indicate that tau pathology appears at a younger age than SPs and most recently Braak and Del Tredici, and Elobeid et al demonstrated tau positive pathology in cases less than 30 years of age. Based on these data, they propose that tau pathology begins to deposit in the locus coeruleus and then spreads from there to other brainstem nuclei and to the entorhinal cortex (EC), perhaps by direct cell to cell transmission. This has led to an alternative hypothesis that subcortical tangle pathology before SP formation represents the earliest stages of tau pathology in sporadic AD (Figure 1). However, other interpretations cannot be excluded, such as this tau pathology is merely an insignificant alternation related to aging, or that soluble oligomeric Aβ accumulation precedes this early tau pathology.
(Enlarge Image)
Figure 1.
Chronological relationships among pathology, clinical symptoms and biomarkers. Based on biomarker studies, β-amyloid protein (Aβ) accumulation appears to start ~20 years before the onset of dementia. Amyloid positron emission tomography (PET) or a decrease in Aβ1–42 levels in CSF may indicate Aβ accumulation in the brain, even in preclinical Alzheimer's disease (AD). Neocortical tau pathology correlates closely with the timing of symptom onset. But, as discussed in the text, these findings need to be reconciled with reports by Braak and colleagues that tau pathology is seen in the brain prior to Aβ pathology, while functional MRI (fMRI) abnormalities may be the earliest biomarker to change in the preclinical phase of AD.11–14 FDG, 2-[18 F]-fluoro-2-deoxy-D-glucose; MCI, mild cognitive impairment.
Aβ biomarker (amyloid PET, Aβ1–42 in CSF) abnormalities precede synaptic dysfunction (FDG-PET) and tau biomarker (tau/p-tau in CSF) abnormalities, followed by brain structural changes (structural MRI) and, finally, cognitive decline (figure 1). However, other studies suggest that functional MRI, which indicates neuronal hyperconnectivity or hypoconnectivity, may show abnormalities before amyloid biomarkers become abnormal, thereby suggesting this may be the earliest biomarker to change in preclinical AD (figure 1). According to the amyloid cascade hypothesis, pharmacological agents that reduce brain Aβ content are supposed to act as effective drugs against AD; several different candidate drugs of this type have been developed. However, clinical trials directed at increasing the clearance or decreasing production of Aβ, which are at different stages of development, have been largely disappointing. Active immunisation with Aβ (AN1792) resulted in impressive clearance of SPs from the brain, as confirmed by pathological examination, but did not prevent progressive cognitive decline, NFT formation or neurodegeneration. Moreover, neither tarenflurbil nor semagacestat (http://files.shareholder.com/downloads/LLY/1921397628x0x395879/54b1f68f-c7b8-4c04-87d1-8c609c21f6f7/LLY_News_2010_8_17_Product.pdf), which act to decrease the production of Aβ, showed any clinical benefits. Most recently, the results on the phase III clinical trials of passive immunisations against Aβ (bapineuzumab and ?solanezumab) were announced (http://www.pfizer.com/news/press_releases/pfizer_press_release.jsp?guid=20120806006130en&source=RSS_2011&page=1; http://newsroom.lilly.com/releasedetail.cfm?releaseid=702211). None of these clinical trials proved significant efficacy of the primary endpoints, although the potential efficacy was not completely denied.
These observations have challenged the assumption that Aβ induces tau mediated neurodegeneration, and the work of Braak et al are consistent with the view that tau pathology emerges autonomously and independently from Aβ, and tau pathology may be the more proximal cause of neurodegeneration in AD. This view is supported by findings in AD mouse models: Aβ immunotherapy in 3×Tg-AD (PS1 (M146V), APP (Swe) and tau (P301L)) mice resulted in a reduction in extracellular SPs and intracellular Aβ accumulation and led to the clearance of less phosphorylated tau pathology; however, hyperphosphorylated tau aggregates were unaffected by Aβ antibody treatment. Additionally, reduction of both soluble Aβ and tau levels, but not a reduction of soluble Aβ levels alone, ameliorated cognitive decline. Therefore, Aβ targeting therapies might exert preventive effects in the preclinical or very early clinical stages of AD, but once cognitive decline appears in association with accumulations of tau pathology, then tau targeting drugs might be necessary for disease modification (Figure 1).
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