Abstract:
:We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer's disease (AD) that requires closer attention in the development of AD therapeutics. Our rationale is fourfold: (i) Glucose uptake is lower in the frontal cortex of people >65 years-old despite cognitive scores that are normal for age. (ii) The regional deficit in brain glucose uptake is present in adults <40 years-old who have genetic or lifestyle risk factors for AD but in whom cognitive decline has not yet started. Examples include young adult carriers of presenilin-1 or apolipoprotein E4, and young adults with mild insulin resistance or with a maternal family history of AD. (iii) Regional brain glucose uptake is impaired in AD and mild cognitive impairment (MCI), but brain uptake of ketones (beta-hydroxybutyrate and acetoacetate), remains the same in AD and MCI as in cognitively healthy age-matched controls. These observations point to a brain fuel deficit which appears to be specific to glucose, precedes cognitive decline associated with AD, and becomes more severe as MCI progresses toward AD. Since glucose is the brain's main fuel, we suggest that gradual brain glucose exhaustion is contributing significantly to the onset or progression of AD. (iv) Interventions that raise ketone availability to the brain improve cognitive outcomes in both MCI and AD as well as in acute experimental hypoglycemia. Ketones are the brain's main alternative fuel to glucose and brain ketone uptake is still normal in MCI and in early AD, which would help explain why ketogenic interventions improve some cognitive outcomes in MCI and AD. We suggest that the brain energy deficit needs to be overcome in order to successfully develop more effective therapeutics for AD. At present, oral ketogenic supplements are the most promising means of achieving this goal.
journal_name
Front Mol Neuroscijournal_title
Frontiers in molecular neuroscienceauthors
Cunnane SC,Courchesne-Loyer A,Vandenberghe C,St-Pierre V,Fortier M,Hennebelle M,Croteau E,Bocti C,Fulop T,Castellano CAdoi
10.3389/fnmol.2016.00053subject
Has Abstractpub_date
2016-07-08 00:00:00pages
53issn
1662-5099journal_volume
9pub_type
杂志文章abstract::Neuronal identity is generated by the cell-surface expression of clustered protocadherin (Pcdh) isoforms. In mice, 58 isoforms from three gene clusters, Pcdhα, Pcdhβ, and Pcdhγ, are differentially expressed in neurons. Since cis-heteromeric Pcdh oligomers on the cell surface interact homophilically with that in other ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00114
更新日期:2017-04-24 00:00:00
abstract::Aim: Traumatic brain injury (TBI) is a leading cause of mortality/morbidity and is associated with chronic neuroinflammation. Melanocortin receptor agonists including adrenocorticotropic hormone (ACTH) ameliorate inflammation and provide a novel therapeutic approach. We examined the effect of long-acting cosyntropin (...
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pub_type: 杂志文章
doi:10.3389/fnmol.2020.00109
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abstract::Neuronal gap junctions formed by connexin36 (Cx36) and chemical synapses share striking similarities in terms of plasticity. Ca2+/calmodulin-dependent protein kinase II (CaMKII), an enzyme known to induce memory formation at chemical synapses, has recently been described to potentiate electrical coupling in the retina...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00206
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abstract::The central, lateral and basolateral amygdala (BLA) nuclei are essential for the formation of long-term memories including emotional and drug-related memories. Studying cellular and molecular mechanisms of memory in amygdala may lead to better understanding of how memory is formed and of fear and addiction-related dis...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2016.00023
更新日期:2016-03-31 00:00:00
abstract::N-methyl-d-aspartate receptors (NMDARs) play an important role in many aspects of nervous system function such as synaptic plasticity and neuronal development. NMDARs are heteromers consisting of an obligate NR1 and most commonly one or two kinds of NR2 subunits. While the receptors have been well characterized in som...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/neuro.02.004.2009
更新日期:2009-09-11 00:00:00
abstract::Alzheimer's disease (AD) pathology is characterized by the aggregation of beta-amyloid (Aβ) and tau in the form of amyloid plaques and neurofibrillary tangles in the brain. It has been found that a synergistic relationship between these two proteins may contribute to their roles in disease progression. However, how Aβ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00268
更新日期:2019-11-08 00:00:00
abstract::Maternal cigarette smoke exposure (SE) causes detrimental changes associated with the development of chronic neurological diseases in the offspring as a result of oxidative mitochondrial damage. Maternal L-Carnitine administration has been shown to reduce renal oxidative stress in SE offspring, but its effect in the b...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00033
更新日期:2017-02-13 00:00:00
abstract::In the last decade, bioinformatic analyses of high-throughput proteomics and transcriptomics data have enabled researchers to gain insight into the molecular networks that may underlie lasting changes in synaptic efficacy. Development and utilization of these techniques have advanced the field of learning and memory s...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2017.00045
更新日期:2017-02-24 00:00:00
abstract::In this review we provide an overview of key in vivo experiments undertaken in the cat spinal cord in the 1950s and 1960s, and point out their contributions to our present understanding of glycine receptor (GlyR) function. Importantly, some of these discoveries were made well before an inhibitory receptor, or its agon...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2010.00013
更新日期:2010-05-21 00:00:00
abstract::GABAergic interneuron diversity is a key feature in the brain that helps to create different brain activity patterns and behavioral states. Cell type classification schemes-based on anatomical, physiological and molecular features-have provided us with a detailed understanding of the distinct types that constitute thi...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00115
更新日期:2019-05-07 00:00:00
abstract::Microglial activation and the inflammatory response in the central nervous system (CNS) play important roles in secondary damage after traumatic brain injury (TBI). Transcriptional activation of genes that limit secondary damage to the CNS are mediated by a cis-acting element called the antioxidant responsive element ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00117
更新日期:2018-04-17 00:00:00
abstract::The porcine brain closely resembles the human brain in aspects such as development and morphology. Temporal miRNA profiling in the developing embryonic porcine cortex revealed a distinct set of miRNAs, including miR-34c and miR-204, which exhibited a highly specific expression profile across the time of cortical foldi...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00031
更新日期:2017-02-09 00:00:00
abstract::Using a high resolution in situ hybridization technique we have measured PIEZO1, PIEZO2, and TRPV1 transcripts in mouse dorsal root ganglion (DRG) neurons. Consistent with previous studies, PIEZO2 transcripts were highly expressed in DRG neurons of all sizes, including most notably the largest diameter neurons implica...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00178
更新日期:2019-07-19 00:00:00
abstract::The degeneration of dopaminergic neurons during Parkinson's disease (PD) is intimately linked to malfunction of α-synuclein (αSyn), the main component of the proteinaceous intracellular inclusions characteristic for this pathology. The cytotoxicity of αSyn has been attributed to disturbances in several biological proc...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00207
更新日期:2017-06-30 00:00:00
abstract::Microglia are the innate sentinels of the central nervous system (CNS) and are responsible for the homeostasis and immune defense of the CNS. Under the influence of the local environment and cell-cell interaction, microglia exhibit a multidimensional and context-dependent phenotypes that can be cytotoxic and neuroprot...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2018.00158
更新日期:2018-05-14 00:00:00
abstract::Proteolytic processing of the Amyloid Precursor Protein (APP) produces beta-amyloid (Aβ) peptide fragments that accumulate in Alzheimer's Disease (AD), but APP may also regulate multiple aspects of neuronal development, albeit via mechanisms that are not well understood. APP is a member of a family of transmembrane gl...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2016.00130
更新日期:2016-11-25 00:00:00
abstract::Growth of postmitotic neurons occurs during different stages of development, including metamorphosis, and may also be part of neuronal plasticity and regeneration. Recently we showed that growth of post-mitotic neuroendocrine cells expressing the basic helix loop helix (bHLH) transcription factor Dimmed (Dimm) in Dros...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2016.00097
更新日期:2016-10-13 00:00:00
abstract::Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. It is caused by the overexpansion of cytosine-guanine-guanine (CGG) trinucleotide in Fmr1 gene, resulting in complete loss of the fragile X mental retardation protein (FMRP). Previous studies using Fmr1 knockout (Fmr1 KO) mice have ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00495
更新日期:2019-01-17 00:00:00
abstract::Inhibition of nerve growth and plasticity in the CNS is to a large part mediated by Nogo-like signaling, now encompassing a plethora of ligands, receptors, co-receptors and modulators. Here we describe the distribution and levels of mRNA encoding 11 key genes involved in Nogo-like signaling (Nogo-A, Oligodendrocyte-My...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00094
更新日期:2017-04-11 00:00:00
abstract::The astrocyte-specific enzyme glutamine synthetase (GS), which catalyzes the amidation of glutamate to glutamine, plays an essential role in supporting neurotransmission and in limiting NH4+ toxicity. Accordingly, deficits in GS activity contribute to epilepsy and neurodegeneration. Despite its central role in brain p...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00120
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abstract::Unlike a number of amyloid-forming proteins, stefins, and in particular stefin B (cystatin B) form amyloids under conditions where the native state predominates. In order to trigger oligomerization processes, the stability of the protein needs to be compromised, favoring structural re-arrangement however, accelerating...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2012.00094
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abstract::The term neurodevelopmental disorder (NDD) is an umbrella term used to group together a heterogeneous class of disorders characterized by disruption in cognition, emotion, and behavior, early in the developmental timescale. These disorders are heterogeneous, yet they share common behavioral symptomatology as well as o...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2018.00132
更新日期:2018-04-24 00:00:00
abstract::Long non-coding RNAs (LncRNAs) are essential epigenetic regulators with critical roles in tumor initiation and malignant progression. However, the roles and mechanisms of aberrantly expressed lncRNAs in the pathogenesis of gliomas are not fully understood. With the development of deep sequencing analyses, an extensive...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2017.00053
更新日期:2017-02-28 00:00:00
abstract::Control of proper protein synthesis, function, and turnover is essential for the health of all cells. In neurons these demands take on the additional importance of supporting and regulating the highly dynamic connections between neurons that are necessary for cognitive function, learning, and memory. Regulating multip...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2014.00063
更新日期:2014-07-08 00:00:00
abstract::Transcription factors regulate multiple processes during brain development and in the adult brain, from brain patterning to differentiation and maturation of highly specialized neurons as well as establishing and maintaining the functional neuronal connectivity. The members of the zinc-finger transcription factor fami...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2020.00051
更新日期:2020-04-08 00:00:00
abstract::The tyrosine kinase Fyn plays an important role in synaptic plasticity, learning, and memory. Here we report that Fyn is activated in response to 15 min D1 receptor (D1R) but not D2 receptor (D2R) stimulation specifically in the dorsomedial striatum (DMS) of mice but not in the other substriatal regions, the dorsolate...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00273
更新日期:2017-08-31 00:00:00
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journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00433
更新日期:2018-01-04 00:00:00
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journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00432
更新日期:2017-12-22 00:00:00
abstract::[This corrects the article on p. 257 in vol. 10, PMID: 28855859.]. ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,已发布勘误
doi:10.3389/fnmol.2017.00392
更新日期:2017-11-20 00:00:00
abstract::[This corrects the article DOI: 10.3389/fnmol.2018.00312.]. ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,已发布勘误
doi:10.3389/fnmol.2019.00079
更新日期:2019-04-04 00:00:00