GABA and glutamate moderate beta-amyloid related functional connectivity in cognitively unimpaired old-aged adults

Quevenco, Frances C.; Schreiner, Simon J.; Preti, Maria Giulia; Bergen, Jiri M.G. Van; Kirchner, Thomas; Wyss, Michael; Steininger, Stephanie C.; Gietl, Anton; Leh, Sandra E.; Buck, Alfred; Pruessmann, Klaas P.; Höck, Christoph; Nitsch, Roger M.; Henning, A; Ville, Dimitri Van De; Unschuld, Paul G.

doi:10.1016/j.nicl.2019.101776

Cited by 25 publications

(31 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Severe deficits in the cholinergic system have been linked to AD, and cholinergic neurons in the nucleus basalis of Meynert have been identified as a progression marker of cognitive decline in AD (Whitehouse et al ; Whitehouse et al ). Other neurotransmitter systems, including NE, serotonin, glutamate, and somatostatin, are believed to contribute to the disease (Esposito et al ; Solarski et al ; Park et al ; Quevenco et al ; Metaxas et al ). Currently, no effective therapeutics are available to either halt or reverse the progression of AD that is likely because of its polygenic nature (Gold ).…”

Section: Dβh In Neurodegenerative Diseasementioning

confidence: 99%

Dopamine beta‐hydroxylase and its genetic variants in human health and disease

Gonzalez-Lopez

Vrana

2019

Journal of Neurochemistry

View full text Add to dashboard Cite

Dopamine beta-hydroxylase (DbH) is an essential neurotransmitter-synthesizing enzyme that catalyzes the formation of norepinephrine (NE) from dopamine and has been extensively studied since its discovery in the 1950s. NE serves as a neurotransmitter in both the central and peripheral nervous systems and is the precursor to epinephrine synthesis in the brain and adrenal medulla. Alterations in noradrenergic signaling have been linked to both central nervous system and peripheral pathologies. DbH protein, which is found in circulation, can, therefore, be evaluated as a marker of norepinephrine function in a plethora of different disorders and diseases. In many of these diseases, DbH protein availability and activity are believed to contribute to disease presentation or select symptomology and are believed to be under strong genetic control. Alteration in the DbH protein by genetic polymorphisms may result in DbH becoming ratelimiting and directly contributing to lower NE and epinephrine levels and disease. With the completion of the human genome project and the advent of next-generation sequencing, new insights have been gained into the existence of naturally occurring DbH sequencing variants (genetic polymorphisms) in disease. Also, biophysical tools coupled with genetic sequences are illuminating structure-function relationships within the enzyme. In this review, we discuss the role of genetic variants in DbH and its role in health and disease.

show abstract

Section: Dβh In Neurodegenerative Diseasementioning

confidence: 99%

Dopamine beta‐hydroxylase and its genetic variants in human health and disease

Gonzalez-Lopez

Vrana

2019

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…Some studies have suggested that the loss of balance of excitatory versus inhibitory neurotransmitter systems may underline early cognitive deficits and occasional epileptiform activity in AD (Goutagny et al, 2013; Petrache et al, 2019; Stoiljkovic, Kelley, Horvath, & Hajos, 2018; Vossel et al, 2016). The imbalance of glutamatergic and GABAergic neurotransmission may also be interrupted by oAβ (Quevenco et al, 2019). This and other evidence support an imbalance between excitatory and inhibitory transmission that may contribute to cognitive deficits in AD patients (Selten, van Bokhoven, & Nadif Kasri, 2018; Vico Varela, Etter, & Williams, 2019).…”

Section: Introductionmentioning

confidence: 99%

A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer’s brain

Selkoe

2020

Journal of Neurochemistry

189

170

View full text Add to dashboard Cite

It is increasingly accepted that early cognitive impairment in Alzheimer's disease results in considerable part from synaptic dysfunction caused by the accumulation of a range of oligomeric assemblies of amyloid β‐protein (Aβ). Most studies have used synthetic Aβ peptides to explore the mechanisms of memory deficits in rodent models, but recent work suggests that Aβ assemblies isolated from human (AD) brain tissue are far more potent and disease‐relevant. Although reductionist experiments show Aβ oligomers to impair synaptic plasticity and neuronal viability, the responsible mechanisms are only partly understood. Glutamatergic receptors, GABAergic receptors, nicotinic receptors, insulin receptors, the cellular prion protein, inflammatory mediators, and diverse signaling pathways have all been suggested. Studies using AD brain‐derived soluble Aβ oligomers suggest that only certain bioactive forms (principally small, diffusible oligomers) can disrupt synaptic plasticity, including by binding to plasma membranes and changing excitatory–inhibitory balance, perturbing mGluR, PrP, and other neuronal surface proteins, down‐regulating glutamate transporters, causing glutamate spillover, and activating extrasynaptic GluN2B‐containing NMDA receptors. We synthesize these emerging data into a mechanistic hypothesis for synaptic failure in Alzheimer's disease that can be modified as new knowledge is added and specific therapeutics are developed.

show abstract

“…The wide spread loss of GABA levels shown in these studies may simply be related to AD-associated neuronal loss. A recent study has shown that alteration of functional brain networks in AD are more related to GABAergic dysfunction than glutamatergic dysfunction in humans 62 . In an APPxPS1 mouse model of AD, Jo et al .…”

Section: Discussionmentioning

confidence: 99%

Dual dose-dependent effects of fingolimod in a mouse model of Alzheimer’s disease

Carreras

Aytan

Choi

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Lipid metabolism is abnormal in Alzheimer’s disease (AD) brain leading to ceramide and sphingosine accumulation and reduced levels of brain sphingosine-1-phosphate (S1P). We hypothesize that changes in S1P signaling are central to the inflammatory and immune-pathogenesis of AD and the therapeutic benefits of fingolimod, a structural analog of sphingosine that is FDA approved for the treatment of multiple sclerosis. We recently reported that the neuroprotective effects of fingolimod in 5xFAD transgenic AD mice treated from 1–3 months of age were greater at 1 mg/kg/day than at 5 mg/kg/day. Here we performed a dose-response study using fingolimod from 0.03 to 1 mg/kg/day in 5xFAD mice treated from 1–8 months of age. At 1 mg/kg/day, fingolimod decreased both peripheral blood lymphocyte counts and brain Aβ levels, but at the lowest dose tested (0.03 mg/kg/day), we detected improved memory, decreased activation of brain microglia and astrocytes, and restored hippocampal levels of GABA and glycerophosphocholine with no effect on circulating lymphocyte counts. These findings suggests that, unlike the case in multiple sclerosis, fingolimod may potentially have therapeutic benefits in AD at low doses that do not affect peripheral lymphocyte function.

show abstract

GABA and glutamate moderate beta-amyloid related functional connectivity in cognitively unimpaired old-aged adults

Cited by 25 publications

References 94 publications

Dopamine beta‐hydroxylase and its genetic variants in human health and disease

Dopamine beta‐hydroxylase and its genetic variants in human health and disease

A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer’s brain

Dual dose-dependent effects of fingolimod in a mouse model of Alzheimer’s disease

Contact Info

Product

Resources

About