Alzheimer’s Disease: Lessons Learned from Amyloidocentric Clinical Trials

Soejitno, Andreas; Tjan, Anastasia; Purwata, Thomas Eko

doi:10.1007/s40263-015-0257-8

Cited by 27 publications

(20 citation statements)

References 127 publications

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“…Moreover, our finding that BDNF loss may mediate tau neurotoxicity down-stream of Aβ has profound implications for therapeutic intervention in AD. Clinical trials targeting Aβ have, so far, been ineffective (Soejitno et al, 2015; Godyń et al, 2016). This suggests that current monotherapies used to alleviate AD symptoms by targeting Aβ pathology alone may not be sufficient, and that combined treatments targeting multiple molecules, including tau, may be desirable (Mufson et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Tau downregulates BDNF expression in animal and cellular models of Alzheimer's disease

Rosa

Mahendram

et al. 2016

Neurobiology of Aging

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In Alzheimer’s disease (AD), soluble tau accumulates and deposits as neurofibrillary tangles (NFTs). However, a precise toxic mechanism of tau is not well understood. We hypothesized that over-expression of wild-type tau down-regulates brain-derived neurotrophic factor (BDNF), a neurotrophic peptide essential for learning and memory. Two transgenic mouse models of human tau expression and human tau (hTau40)-transfected human neuroblastoma (SH-SY5Y) cells were used to examine the effect of excess or pathologically modified wild-type human tau on BDNF expression. Both transgenic mouse models, with or without NFTs, as well as hTau40-SH-SY5Y cells significantly down-regulated BDNF mRNA compared to controls. Similarly, transgenic mice over-expressing amyloid-β significantly down-regulated BDNF expression. However, when crossed with tau knockout mice, the resulting animals exhibited BDNF levels that were not statistically different from wild-type mice. These results demonstrate that excess or pathologically modified wild-type human tau down-regulates BDNF and that neither a mutation in tau nor the presence of NFTs is required for toxicity. Moreover, our findings suggest that tau at least partially mediates amyloid-β-induced BDNF down-regulation. Therefore, AD treatments targeting Aβ alone may not be effective without considering the impact of tau pathology on neurotrophic pathways.

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Section: Discussionmentioning

confidence: 99%

Tau downregulates BDNF expression in animal and cellular models of Alzheimer's disease

Rosa

Mahendram

et al. 2016

Neurobiology of Aging

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“…While many studies have concentrated on the activation of MAPK signaling, the mechanisms that lead to its termination are less studied. DUSP1 dephosphorylates and inactivates preferably p38 and JNK and, to a lesser extent, ERK1/255 and may be a viable target for AD therapies given the difficulties associated with the amyloid reduction clinical trials to date5657.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Neurotrophin Signaling through the Glucocorticoid Receptor Pathway Causes Tau Neuropathology

Arango-Lievano

Peguet

Catteau

et al. 2016

Sci Rep

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Glucocorticoid resistance is a risk factor for Alzheimer’s disease (AD). Molecular and cellular mechanisms of glucocorticoid resistance in the brain have remained unknown and are potential therapeutic targets. Phosphorylation of glucocorticoid receptors (GR) by brain-derived neurotrophic factor (BDNF) signaling integrates both pathways for remodeling synaptic structure and plasticity. The goal of this study is to test the role of the BDNF-dependent pathway on glucocorticoid signaling in a mouse model of glucocorticoid resistance. We report that deletion of GR phosphorylation at BDNF-responding sites and downstream signaling via the MAPK-phosphatase DUSP1 triggers tau phosphorylation and dendritic spine atrophy in mouse cortex. In human cortex, DUSP1 protein expression correlates with tau phosphorylation, synaptic defects and cognitive decline in subjects diagnosed with AD. These findings provide evidence for a causal role of BDNF-dependent GR signaling in tau neuropathology and indicate that DUSP1 is a potential target for therapeutic interventions.

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“…To date, no efficient therapy is available for AD 4 , a disease with a strong component of amyloid-β (Aβ) aggregation 1 . Clinical trials for AD focused primarily on counteracting Aβ aggregation in the brain, considered the key pathogenic mechanism 5 . However, AD is a complex multifactorial disease 6 and mitochondrial dysfunction emerged as a common pathological hallmark 7 .…”

mentioning

confidence: 99%

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Sorrentino

Romani

Mouchiroud

et al. 2017

Nature

512

424

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Alzheimer’s disease (AD) is a common and devastating disease characterized by the aggregation of amyloid-β peptide (Aβ), yet we know relatively little about the underlying molecular mechanisms or how to treat AD patients. Here, we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in Aβ proteotoxic diseases in human, mouse and C. elegans, and which involves the UPRmt and mitophagy pathways. Using the worm model of Aβ proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed the induction of this mitochondrial stress response as key to maintain mitochondrial proteostasis and health. Importantly, boosting mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms, and in AD transgenic mice. Our data support the relevance of enhancing mitochondrial proteostasis to delay Aβ proteotoxic diseases, such as AD.

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Alzheimer’s Disease: Lessons Learned from Amyloidocentric Clinical Trials

Cited by 27 publications

References 127 publications

Tau downregulates BDNF expression in animal and cellular models of Alzheimer's disease

Tau downregulates BDNF expression in animal and cellular models of Alzheimer's disease

Deletion of Neurotrophin Signaling through the Glucocorticoid Receptor Pathway Causes Tau Neuropathology

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

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