A Randomized, Controlled Trial of Doxycycline and Rifampin for Patients with Alzheimer's Disease

Loeb, Mark; Molloy, D. William; Śmieja, Marek; Standish, Tim; Goldsmith, Charles H.; Mahony, J. B.; Smith, Stephanie; Borrie, Michael; Decoteau, Earl; Davidson, Warren; McDougall, Allan; Gnarpe, Judy; O’Donnell, Martin; Chernesky, Max

doi:10.1111/j.1532-5415.2004.52109.x

Cited by 207 publications

(157 citation statements)

References 27 publications

(65 reference statements)

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“…These findings indicate that boosting mitochondrial function and proteostasis may decrease the formation of detrimental protein aggregates in the context of proteotoxic disease, typified by reduced mitochondrial activity and loss of proteostasis. Together with initial evidence suggesting potential benefits of targeting dysfunctional mitochondria in AD 26–28,40,41 and in view of recent findings linking mitochondrial stress to the induction of cytosolic proteostasis mechanisms 42–45 , our data support the concept that enhancing mitochondrial proteostasis may hold promise to manage pervasive Aβ proteopathies, such as AD.…”

Section: Discussionsupporting

confidence: 84%

“…5h,i). These results add to observations of in vitro 26 and in vivo studies in AD flies 27 and patients 28 , which suggested that dox treatment may ameliorate AD and Aβ aggregation. Recently, the regulation of the mitochondrial stress responses in mammals, including dox-dependent mitochondrial stress, was shown to rely on the activation of the integrated stress response (ISR) and on the transcription factor ATF4 29–31 .…”

Section: Reducing Mitochondrial Translation Lowers Aβ Proteotoxicitysupporting

confidence: 78%

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Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Sorrentino

Romani

Mouchiroud

et al. 2017

Nature

510

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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Section: Discussionsupporting

confidence: 84%

Section: Reducing Mitochondrial Translation Lowers Aβ Proteotoxicitysupporting

confidence: 78%

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Sorrentino

Romani

Mouchiroud

et al. 2017

Nature

510

424

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“…It was concluded that use of antibacterial compounds may not have had any effect on the treatment of C. pneumoniae but had a beneficial effect on cognitive decline in AD (193). This might be related to prevention or attenuation of a number of peripheral infections or dampening down the proinflammatory cytokine response.…”

mentioning

confidence: 99%

“…In a study of subjects with mild to moderate AD, a 3-month course of doxycycline and rifampicin reduced cognitive deterioration during a 6 months' follow-up interval (193). It was concluded that use of antibacterial compounds may not have had any effect on the treatment of C. pneumoniae but had a beneficial effect on cognitive decline in AD (193).…”

mentioning

confidence: 99%

Inflammasome Involvement in Alzheimer’s Disease

Olsen

Singhrao

2016

JAD

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Alzheimer's disease (AD) is a scourge of longevity that will drain enormous resources from public health budgets in the future. Currently, there is no diagnostic biomarker and/or treatment for this most common form of dementia in humans. AD can be of early familialonset or sporadic with a late-onset. Apart from the two main hallmarks, amyloid-beta and neurofibrillary tangles, inflammation is a characteristic feature of AD neuropathology.Inflammation may be caused by a local central nervous system insult and/or by peripheral infections. Numerous microorganisms are suspected in AD brains ranging from bacteria (mainly oral and non-oral Treponema species), viruses (Herpes simplex type I) and yeasts (Candida species). A causal relationship between periodontal pathogens/non-oral Treponema species of bacteria has been proposed via the amyloid-beta and inflammatory links.Periodontitis constitutes a peripheral oral infection that can provide the brain with intact bacteria and virulence factors and inflammatory mediators due to daily, transient bacteraemias. If and when genetic risk factors meet environmental risk factors in the brain, disease is expressed, in which neurocognition may be impacted, leading to the development of dementia. To achieve the goal of finding a diagnostic biomarker and possible prophylactic treatment for AD, there is an initial need to solve the etiological puzzle contributing to its pathogenesis. This review therefore addresses oral infection as the plausible aetiology of late onset AD (LOAD). ___________________________________________________________________________Keywords: Alzheimer's disease; pathogenesis; microorganisms; oral bacteria; direct cause 3 Alzheimer's disease (AD) is a neurodegenerative disease and the most common example of a group of diseases that manifest as dementia. It is associated with atrophy and specific neuronal death particularly in the hippocampal region of the brain (1). Research into AD pathogenesis, has flagged two main categories of the disease: the familial onset presentation accounts for around 2% of all AD cases and the sporadic form of late-onset AD also referred to as LOAD constitutes approximately 98% of the cases. LOAD displays genetic susceptibility traits of which the well-known risk factor is inheritance of the apolipoprotein (APOEɛ4) gene allele (2) and, appears to require an environmental factor for disease expression. For example a pathogen-host interaction can exacerbate neurocognition in some elderly individuals who if in their 80+ years likely become diagnosed with LOAD (3, 4). The rationale for this review therefore is to try to explain the aetiology in the vast proportion of LOAD cases that relies upon common risk factors. Several scientists have proposed, one of these to be peripheral infections (5-11), and the accompanying systemic and local inflammatory mediators (11)(12)(13). Of these, the plausible risk from oral infection is the main focus of this review. PREVALENCE OF ADAD is a burden of longevity resulting from the superior qualit...

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“…The olfactory epithelium has been proposed as the primary infectious site and the pathogen seems to reach to the olfactory bulb and olfactory cortex and then neuronal damage may progress (Balin & Appelt, 2001). Long term antibiotic therapy, including doxycycline and rifampin, slowed the course of cognitive impairment (Loeb et al, 2004). Metal protein attenuating compounds have been shown to decrease beta amyloid plaques in animal models and antiprotozoal metal chelator clioquinol was used for treatment (Finefrock et al, 2003, Cahoon, 2009.…”

Section: Chlamydia and Neurologic Disordersmentioning

confidence: 99%