Accumulation and age-related elevation of amyloid-β within basal forebrain cholinergic neurons in the rhesus monkey

Norvin, Daphne; Kım, Garam; Baker-Nigh, Alaina; Geula, Changiz

doi:10.1016/j.neuroscience.2015.04.011

Cited by 13 publications

(7 citation statements)

References 46 publications

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“…NGF is a pleiotropic factor for cholinergic neurons of the basal forebrain, the main target of Alzheimer's disease (AD) pathology. Septal cholinergic neurons have been shown to accumulate intracellular amyloid during aging and AD, thus affecting neuronal activity and cognition in rodents, monkeys and humans (Baker‐Nigh et al ., ; Norvin et al ., ). The data presented in this study indicate that NGF downregulates the phosphorylation of APP at the neuron‐specific residue T668, promotes APP binding with TrkA, and favours APP trafficking to the Golgi, at the expense of BACE interaction and cleavage.…”

Section: Discussionmentioning

confidence: 97%

NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer's disease

et al. 2016

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SummaryNGF has been implicated in forebrain neuroprotection from amyloidogenesis and Alzheimer's disease (AD). However, the underlying molecular mechanisms are still poorly understood. Here, we investigated the role of NGF signalling in the metabolism of amyloid precursor protein (APP) in forebrain neurons using primary cultures of septal neurons and acute septo‐hippocampal brain slices. In this study, we show that NGF controls the basal level of APP phosphorylation at Thr668 (T668) by downregulating the activity of the Ser/Thr kinase JNK(p54) through the Tyr kinase signalling adaptor SH2‐containing sequence C (ShcC). We also found that the specific NGF receptor, Tyr kinase A (TrkA), which is known to bind to APP, fails to interact with the fraction of APP molecules phosphorylated at T668 (APPpT668). Accordingly, the amount of TrkA bound to APP is significantly reduced in the hippocampus of ShcC KO mice and of patients with AD in which elevated APPpT668 levels are detected. NGF promotes TrkA binding to APP and APP trafficking to the Golgi, where APP–BACE interaction is hindered, finally resulting in reduced generation of sAPPβ, CTFβ and amyloid‐beta (1‐42). These results demonstrate that NGF signalling directly controls basal APP phosphorylation, subcellular localization and BACE cleavage, and pave the way for novel approaches specifically targeting ShcC signalling and/or the APP–TrkA interaction in AD therapy.

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Section: Discussionmentioning

confidence: 97%

NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer's disease

et al. 2016

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“…Reuptake of amyloid-β peptides will then result in disintegration of BAβACs, the return of acetylcholine levels to the initial steady-state balance, and the initial astroglial status. Indeed very recent reports show that cholinergic neurons are the main neuronal population in the brain that contains intracellular amyloid-β peptides ( Baker-Nigh et al , 2015 ; Norvin et al , 2015 ). However, in the Alzheimer’s disease brain, particularly in the presence of APOE4 gene, a high APOE protein ( Darreh-Shori et al , 2011 b ) disturbs the formation, the disintegration or both by causing dysfunctional amyloid-β reuptake (clearance) by neurons or astroglial cells.…”

Section: Discussionmentioning

confidence: 99%

“…The main characteristic of BAβACs is that they can oscillate between a slow and ultrafast state of acetylcholine hydrolysis, depending on access to amyloid-β peptides ( Darreh-Shori et al , 2011 a , b ). Intriguingly, cholinergic neurons seem to be the main neuronal populations in the brain that contain intraneuronal amyloid-β in both healthy and diseased brain ( Baker-Nigh et al , 2015 ; Norvin et al , 2015 ). We have thus hypothesized that an amyloid-β induced allosteric hyperactivation of these enzymes represents a native physiological function for the universal production and nerve activity synchronized amyloid-β release ( Cirrito et al , 2005 ).…”

Section: Introductionmentioning

confidence: 99%

Amyloid-β peptides act as allosteric modulators of cholinergic signalling through formation of soluble BAβACs

Kumar

Nordberg

Darreh‐Shori

2015

Brain

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“…In rhesus monkeys, a significant age-related A β increase was found in the basal forebrain cholinergic neurons [ 123 ]. Human PET studies showed that about one-third of healthy elderly individuals manifested elevated levels of A β deposition in the frontal, cingulated, and parietal areas and in the DMN, even years before clinical cognitive deficits [ 124 , 125 ].…”

Section: Beta-amyloidsmentioning

confidence: 99%

Are Anxiety Disorders Associated with Accelerated Aging? A Focus on Neuroprogression

Perna

Iannone²,

Alciati³

et al. 2016

Neural Plasticity

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Anxiety disorders (AnxDs) are highly prevalent throughout the lifespan, with detrimental effects on daily-life functioning, somatic health, and quality of life. An emerging perspective suggested that AnxDs may be associated with accelerated aging. In this paper, we explored the association between AnxDs and hallmarks of accelerated aging, with a specific focus on neuroprogression. We reviewed animal and human findings that suggest an overlap between processes of impaired neurogenesis, neurodegeneration, structural, functional, molecular, and cellular modifications in AnxDs, and aging. Although this research is at an early stage, our review suggests a link between anxiety and accelerated aging across multiple processes involved in neuroprogression. Brain structural and functional changes that accompany normal aging were more pronounced in subjects with AnxDs than in coevals without AnxDs, including reduced grey matter density, white matter alterations, impaired functional connectivity of large-scale brain networks, and poorer cognitive performance. Similarly, molecular correlates of brain aging, including telomere shortening, Aβ accumulation, and immune-inflammatory and oxidative/nitrosative stress, were overrepresented in anxious subjects. No conclusions about causality or directionality between anxiety and accelerated aging can be drawn. Potential mechanisms of this association, limitations of the current research, and implications for treatments and future studies are discussed.

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Accumulation and age-related elevation of amyloid-β within basal forebrain cholinergic neurons in the rhesus monkey

Cited by 13 publications

References 46 publications

NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer's disease

NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer's disease

Amyloid-β peptides act as allosteric modulators of cholinergic signalling through formation of soluble BAβACs

Are Anxiety Disorders Associated with Accelerated Aging? A Focus on Neuroprogression

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