Decades of research indicate mitochondria from Alzheimer's disease (AD) patients differ from those of non-AD individuals. Initial studies revealed structural differences, and subsequent studies ...showed functional deficits. Observations of structure and function changes prompted investigators to consider the consequences, significance, and causes of AD-related mitochondrial dysfunction. Currently, extensive research argues mitochondria may mediate, drive, or contribute to a variety of AD pathologies. The perceived significance of these mitochondrial changes continues to grow, and many currently believe AD mitochondrial dysfunction represents a reasonable therapeutic target. Debate continues over the origin of AD mitochondrial changes. Some argue amyloid-β (Aβ) induces AD mitochondrial dysfunction, a view that does not challenge the amyloid cascade hypothesis and that may in fact help explain that hypothesis. Alternatively, data indicate mitochondrial dysfunction exists independent of Aβ, potentially lies upstream of Aβ deposition, and suggest a primary mitochondrial cascade hypothesis that assumes mitochondrial pathology hierarchically supersedes Aβ pathology. Mitochondria, therefore, appear at least to mediate or possibly even initiate pathologic molecular cascades in AD. This review considers studies and data that inform this area of AD research.
Dysfunction of cell bioenergetics is a common feature of neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). Disrupted energy utilization implicates mitochondria at its ...nexus. This review summarizes some of the evidence that points to faulty mitochondrial function in AD and highlights past and current therapeutic development efforts. Classical neuropathological hallmarks of disease (β‐amyloid and τ) and sporadic AD risk genes (APOE) may trigger mitochondrial disturbance, yet mitochondrial dysfunction may incite pathology. Preclinical and clinical efforts have overwhelmingly centred on the amyloid pathway, but clinical trials have yet to reveal clear‐cut benefits. AD therapies aimed at mitochondrial dysfunction are few and concentrate on reversing oxidative stress and cell death pathways. Novel research efforts aimed at boosting mitochondrial and bioenergetic function offer an alternative treatment strategy. Enhancing cell bioenergetics in preclinical models may yield widespread favourable effects that could benefit persons with AD.
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This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc
Mitochondria and brain bioenergetics are increasingly thought to play an important role in Alzheimer's disease (AD).
Data that support this view are discussed from the perspective of the amyloid ...cascade hypothesis, which assumes beta-amyloid perturbs mitochondrial function, and from an opposite perspective that assumes mitochondrial dysfunction promotes brain amyloidosis. A detailed review of cytoplasmic hybrid (cybrid) studies, which argue mitochondrial DNA (mtDNA) contributes to sporadic AD, is provided. Recent AD endophenotype data that further suggest an mtDNA contribution are also summarized.
Biochemical, molecular, cybrid, biomarker, and clinical data pertinent to the mitochondria-bioenergetics-AD nexus are synthesized and the mitochondrial cascade hypothesis, which represents a mitochondria-centric attempt to conceptualize sporadic AD, is discussed.
Viable Alzheimer's disease (AD) hypotheses must account for its age-dependence; commonality; association with amyloid precursor protein, tau, and apolipoprotein E biology; connection with vascular, ...inflammation, and insulin signaling changes; and systemic features. Mitochondria and parameters influenced by mitochondria could link these diverse characteristics. Mitochondrial biology can initiate changes in pathways tied to AD and mediate the dysfunction that produces the clinical phenotype. For these reasons, conceptualizing a mitochondrial cascade hypothesis is a straightforward process and data accumulating over decades argue the validity of its principles. Alternative AD hypotheses may yet account for its mitochondria-related phenomena, but absent this happening a primary mitochondrial cascade hypothesis will continue to evolve and attract interest.
Sample size determination for open-ended questions or qualitative interviews relies primarily on custom and finding the point where little new information is obtained (thematic saturation). Here, we ...propose and test a refined definition of saturation as obtaining the most salient items in a set of qualitative interviews (where items can be material things or concepts, depending on the topic of study) rather than attempting to obtain all the items. Salient items have higher prevalence and are more culturally important. To do this, we explore saturation, salience, sample size, and domain size in 28 sets of interviews in which respondents were asked to list all the things they could think of in one of 18 topical domains. The domains-like kinds of fruits (highly bounded) and things that mothers do (unbounded)-varied greatly in size. The datasets comprise 20-99 interviews each (1,147 total interviews). When saturation was defined as the point where less than one new item per person would be expected, the median sample size for reaching saturation was 75 (range = 15-194). Thematic saturation was, as expected, related to domain size. It was also related to the amount of information contributed by each respondent but, unexpectedly, was reached more quickly when respondents contributed less information. In contrast, a greater amount of information per person increased the retrieval of salient items. Even small samples (n = 10) produced 95% of the most salient ideas with exhaustive listing, but only 53% of those items were captured with limited responses per person (three). For most domains, item salience appeared to be a more useful concept for thinking about sample size adequacy than finding the point of thematic saturation. Thus, we advance the concept of saturation in salience and emphasize probing to increase the amount of information collected per respondent to increase sample efficiency.
Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; ...inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases.
•The mitochondrial cascade hypothesis argues that bioenergetic dysfunction mediates Alzheimer's disease (AD).•It assumes that AD-associated biomarker changes reflect brain aging.•It assumes that a recently proposed AD clinical classification scheme stages brain aging.•It assumes that removing Aβ from symptomatic or presymptomatic individuals will marginally impact cognition.
Genomic investigations of acute myeloid leukemia (AML) have demonstrated that several genes are recurrently mutated, leading to new genomic classifications, predictive biomarkers, and new therapeutic ...targets. Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of all AML cases, with the internal tandem duplication (ITD) representing the most common type of FLT3 mutation (FLT3-ITD; approximately 25% of all AML cases). FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML. The prognostic value of a FLT3 mutation in the tyrosine kinase domain (FLT3-TKD), which has a lower incidence in AML (approximately 7-10% of all cases), is uncertain. Accumulating evidence demonstrates that FLT3 mutational status evolves throughout the disease continuum. This so-called clonal evolution, together with the identification of FLT3-ITD as a negative prognostic marker, serves to highlight the importance of FLT3-ITD testing at diagnosis and again at relapse. Earlier identification of FLT3 mutations will help provide a better understanding of the patient's disease and enable targeted treatment that may help patients achieve longer and more durable remissions. First-generation FLT3 inhibitors developed for clinical use are broad-spectrum, multikinase inhibitors; however, next-generation FLT3 inhibitors are more specific, more potent, and have fewer toxicities associated with off-target effects. Primary and secondary acquired resistance to FLT3 inhibitors remains a challenge and provides a rationale for combining FLT3 inhibitors with other therapies, both conventional and investigational. This review focuses on the pathological and prognostic role of FLT3 mutations in AML, clinical classification of the disease, recent progress with next-generation FLT3 inhibitors, and mechanisms of resistance to FLT3 inhibitors.
Neuroketotherapeutics represent a class of bioenergetic medicine therapies that feature the induction of ketosis. These therapies include medium-chain triglyceride supplements, ketone esters, ...fasting, strenuous exercise, the modified Atkins diet, and the classic ketogenic diet. Extended experience reveals persons with epilepsy, especially pediatric epilepsy, benefit from ketogenic diets although the mechanisms that underlie its effects remain unclear. Data indicate ketotherapeutics enhance mitochondrial respiration, promote neuronal long-term potentiation, increase BDNF expression, increase GPR signaling, attenuate oxidative stress, reduce inflammation, and alter protein post-translational modifications via lysine acetylation and β-hydroxybutyrylation. These properties have further downstream implications involving Akt, PLCγ, CREB, Sirtuin, and mTORC pathways. Further studies of neuroketotherapeutics will enhance our understanding of ketone body molecular biology, and reveal novel central nervous system therapeutic applications.
•Several approaches exist for achieving ketosis.•Ketosis approaches produce pervasive molecular effects.•These approaches may potentially benefit multiple neurologic conditions.
Alzheimer's disease (AD) features mitochondrial dysfunction and altered metabolism. Other pathologies could drive these changes, or alternatively these changes could drive other pathologies. In ...considering this question, it is worth noting that perturbed AD patient mitochondrial and metabolism dysfunction extend beyond the brain and to some extent define a systemic phenotype. It is difficult to attribute this systemic phenotype to brain beta-amyloid or tau proteins. Conversely, mitochondria increasingly appear to play a critical role in cell proteostasis, which suggests that mitochondrial dysfunction may promote protein aggregation. Mitochondrial and metabolism-related characteristics also define AD endophenotypes in cognitively normal middle-aged individuals, which suggests that mitochondrial and metabolism-related AD characteristics precede clinical decline. Genetic analyses increasingly implicate mitochondria and metabolism-relevant genes in AD risk. Collectively these factors suggest that mitochondria are more relevant to the causes of AD than its consequences, and support the view that a mitochondrial cascade features prominently in AD. This chapter reviews the case for mitochondrial and metabolism dysfunction in AD and the challenges of proving that a primary mitochondrial cascade is pertinent to the disease.
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