Fats, Friends or Foes: Investigating the Role of Short- and Medium-Chain Fatty Acids in Alzheimer’s Disease

Ameen, Aishat O.; Freude, Kristine; Aldana, Blanca I.

doi:10.3390/biomedicines10112778

Cited by 14 publications

(8 citation statements)

References 124 publications

(211 reference statements)

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“…Our functional analysis of the GM was prompted by research findings showing the ability of SCFAs to ameliorate certain AD hallmarks in mouse models [ 55 ], however our results, somewhat surprisingly, showed only reduced levels of anti-inflammatory propionic acid and a higher abundance of valeric acid in WT DSS mice compared to WT controls, while no differences were observed for Tg2576 DSS animals.…”

Section: Discussionmentioning

confidence: 67%

Experimental colitis in young Tg2576 mice accelerates the onset of an Alzheimer’s-like clinical phenotype

Lorenzini,

Zanella,

Sannia

et al. 2024

Alz Res Therapy

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Systemic inflammation and neuroinflammation affect the natural course of the sporadic form of Alzheimer’s disease (AD), as supported by epidemiological and preclinical data, and several epidemiological studies indicate a higher prevalence of AD in patients with inflammatory bowel disease. In this study, we explored whether colitis induced by dextran sulfate sodium (DSS) in young, presymptomatic/preplaque mice worsens and/or anticipates age-dependent cognitive impairment in Tg2576, a widely used mouse model of AD. We demonstrated that DSS colitis induced in young Tg2576 mice anticipates the onset age of learning and memory deficit in the Morris water maze test. To explore potential mechanisms behind the acceleration of cognitive decline in Tg2576 mice by DSS colitis, we focused on gut microbiota, systemic inflammation and neuroinflammation markers. We observed a Firmicutes/Bacteroidetes ratio change in Tg2576 DSS animals comparable to that of elderly Tg2576 mice, suggesting accelerated microbiota aging in Tg2576 DSS mice, a change not observed in C57BL6 DSS mice. We also observed substantial differences between Tg2576 and WT mice in several inflammation and neuroinflammation-related parameters as early as 3 months of age, well before plaque deposition, a picture which evolved rapidly (between 3 and 5.5 months of age) in contrast to Tg2576 and WT littermates not treated with DSS. In detail, following induction of DSS colitis, WT and Tg2576 mice exhibited contrasting features in the expression level of inflammation-evoked astrocyte-associated genes in the hippocampus. No changes in microglial features occurred in the hippocampus between the experimental groups, whereas a reduced glial fibrillary acidic protein immunoreactivity was observed in Tg2576 vs. WT mice. This finding may reflect an atrophic, “loss-of-function” profile, further exacerbated by DSS where a decreased of GFAP mRNA expression level was detected. In conclusion, we suggest that as-yet unidentified peripheral mediators evoked by DSS colitis and involving the gut-brain axis emphasize an astrocyte “loss-of-function” profile present in young Tg2576 mice, leading to impaired synaptic morphological and functional integrity as a very early sign of AD.

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Section: Discussionmentioning

confidence: 67%

Experimental colitis in young Tg2576 mice accelerates the onset of an Alzheimer’s-like clinical phenotype

Lorenzini,

Zanella,

Sannia

et al. 2024

Alz Res Therapy

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“…Unlike longer chain fatty acids which require specific transporters such as CD36, fatty acid transport proteins (FATPs) and carnitine shuttle ( Heidt et al, 2023 ), medium chain fatty acid (MCFA) arising from MCT do not rely on specific transporters to pass through the mitochondrial membrane ( Miyagawa et al, 2018 ; Heidt et al, 2023 ). Through passive diffusion, MCFA can be easily and directly transported into the mitochondrial matrix ( Heidt et al, 2023 ), and enhances beta-oxidation (β-oxidation) rate in hepatocytes, which ultimately increases the serum KB concentration ( Ameen et al, 2022 ). In response to the increased levels of KBs, brain energy metabolism and cognitive functions are improved significantly ( Ameen et al, 2022 ).…”

Section: Ketogenic Dietmentioning

confidence: 99%

“…Through passive diffusion, MCFA can be easily and directly transported into the mitochondrial matrix ( Heidt et al, 2023 ), and enhances beta-oxidation (β-oxidation) rate in hepatocytes, which ultimately increases the serum KB concentration ( Ameen et al, 2022 ). In response to the increased levels of KBs, brain energy metabolism and cognitive functions are improved significantly ( Ameen et al, 2022 ). Increased levels of KB and brain energy might be important especially for the treatment of patients with AD, impaired brain energy metabolism and cognitive dysfunction ( Krikorian et al, 2012 ).…”

Section: Ketogenic Dietmentioning

confidence: 99%

Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer’s disease

Ramezani,

Fernando,

Eslick

et al. 2023

Front. Neurosci.

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Alzheimer’s disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aβ) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aβ, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the β-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aβ, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.

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“…One potential approach involves the use of medium-chain triglycerides, or medium-chain fatty acids, which are usually defined as fatty acids with a chain length of six to ten or twelve carbon atoms. These include caproic acid (C6), caprylic acid (C8), capric acid (C10), and, under certain circumstances, lauric acid (C12) [ 16 , 17 ]. The background to their therapeutic application is based on findings of considerable impairments in glucose metabolism in the brains of patients with dementia [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…This connection is also known as the astrocyte-neuron lactate shuttle (ANLS) [ 24 ]. Furthermore, research has identified other indirect ways, in which MCFAs may beneficially modulate energy metabolism in the brain, for example, by positively affecting aspects of dementia-related mitochondrial dysfunction [ 16 ]. Cell lines from AD mouse models incubated with C10 showed significant positive effects on the mitochondrial respiratory chain, enzyme activity, and an overall increase in mitochondrial number.…”

Section: Introductionmentioning

confidence: 99%

Medium-Chain Triglycerides (MCTs) for the Symptomatic Treatment of Dementia-Related Diseases: A Systematic Review

Meer,

Fischer

2024

Journal of Nutrition and Metabolism

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Pathomechanisms of dementias involve increasing damage to neuronal energy metabolism, resulting in degeneration-related insulin resistance and glucose hypometabolism. In this case, ketone bodies can provide an alternative energy source. Supplementation with medium-chain triglycerides (MCTs), which can induce ketogenesis, may alleviate brain energy deficits and improve neuronal function. This review aims to determine the effectiveness of MCT as a symptomatic treatment approach. The systematic literature search was conducted in April 2023 following the Cochrane Handbook and PRISMA guidelines. A total of 21 studies were included, comprising eight uncontrolled trials and 13 RCTs investigating the effects of MCT on Alzheimer’s disease (AD) and mild cognitive impairment (MCI). A substantial increase in plasma ketone levels and brain metabolic rates was observed. Cognitive assessments showed only occasional or domain-specific performance improvements. The effects on functional abilities or psychological outcomes have been inadequately studied. Besides gastrointestinal side effects, no harmful effects were observed. However, the evidence was severely weakened by heterogeneous and poorly designed study protocols, bias, and conflicts of interest. In conclusion, the ketogenic properties of MCTs may have beneficial effects on brain metabolism in AD and MCI but do not always result in measurable clinical improvement. Current evidence is insufficient to recommend MCT as a comparable symptomatic treatment option.

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Fats, Friends or Foes: Investigating the Role of Short- and Medium-Chain Fatty Acids in Alzheimer’s Disease

Cited by 14 publications

References 124 publications

Experimental colitis in young Tg2576 mice accelerates the onset of an Alzheimer’s-like clinical phenotype

Experimental colitis in young Tg2576 mice accelerates the onset of an Alzheimer’s-like clinical phenotype

Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer’s disease

Medium-Chain Triglycerides (MCTs) for the Symptomatic Treatment of Dementia-Related Diseases: A Systematic Review

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