Acute Down-regulation of BDNF Signaling Does Not Replicate Exacerbated Amyloid-β Levels and Cognitive Impairment Induced by Cholinergic Basal Forebrain Lesion

Turnbull, Marion T.; Boskovic, Zoran; Coulson, Elizabeth J.

doi:10.3389/fnmol.2018.00051

Cited by 18 publications

(25 citation statements)

References 54 publications

(82 reference statements)

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“…cBF neuronal lesioning in a range of mouse AD models worsens many features of AD, including promoting cognitive impairment, and increasing Aβ accumulation, plaque load and inflammation (as observed herein), as well as causing tau hyperphosphorylation, hippocampal degeneration, and reduced BDNF expression (Gil-Bea et al, 2012;Ramos-Rodriguez et al, 2013;Hartig et al, 2014;Laursen et al, 2014;Turnbull et al, 2018). On the other hand, AD model rodents with increased cBF connectivity (Boskovic et al, 2014;Boskovic et al, 2018;Qian et al, 2018) or those which are treated with muscarinic receptor agonists display cognitive improvements and significantly reduced age-dependent A accumulation and inflammation compared to control rodents (Fisher et al, 2016).…”

Section: Cbf Degeneration Is An Early Ad Feature That Can Drive Othersupporting

confidence: 52%

“…In humans, Aβ load correlates with basal forebrain atrophy and dysfunction (Grothe et al, 2014a;Kerbler et al, 2015a;Chiesa et al, 2019), but it is unclear whether cBF degeneration is a cause and/or effect of Aβ accumulation. In mouse models, oligomeric Aβ can induce cBF degeneration (Sotthibundhu et al, 2008;Knowles et al, 2009), whereas cBF degeneration can exacerbate Aβ accumulation (Gil-Bea et al, 2012;Laursen et al, 2014;Turnbull et al, 2018).…”

Section: Cbf Degeneration Is Induced By Cmpt Lesionmentioning

confidence: 99%

“…However, even in the absence of a predisposition to AD pathology, OSA sequelae caused cBF degeneration and cognitive decline. cBF degeneration is associated with mild cognitive impairment in humans (Grothe et al, 2014a) as well as rodents, particularly impairing higher order cognitive functions, including allothetic and egocentric navigation, as measured in place avoidance tasks (Baxter and Chiba, 1999;Hort et al, 2007;Hamlin et al, 2013;Hort et al, 2014;Kerbler et al, 2015b;Turnbull et al, 2018). Although the hippocampal-dependent, spatial memory impairment of cMPT-lesioned APP/PS mice was concurrent with increased Aβ pathology, the coincident cBF neuronal degeneration likely contributed to the behavioural phenotype (Chiesa et al, 2019).…”

Section: Osa Induces Pathological Hallmarks Admentioning

confidence: 99%

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Cholinergic basal forebrain degeneration due to obstructive sleep apnoea increases Alzheimer’s pathology in mice

Qian

Kasas

Milne

et al. 2020

Preprint

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Epidemiological studies indicate that obstructive sleep apnoea is a strong risk factor for the development of Alzheimer's disease but the mechanisms of the risk remain unclear. We developed a method of modelling obstructive sleep apnoea in mice that replicates key features of human obstructive sleep apnoea: altered breathing during sleep, sleep disruption, moderate intermittent hypoxemia and cognitive impairment. When we induced obstructive sleep apnoea in a familialAlzheimer's disease model, the mice displayed exacerbation of cognitive impairment and pathological features of Alzheimer's disease, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons.These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the neurodegeneration was mediated by the oxygen-sensitive p75 neurotrophin receptor and hypoxia inducible factor 1 alpha activity. Furthermore, restoring blood oxygen levels during sleep to prevent intermittent hypoxia prevented the pathological changes induced by the OSA. These findings provide a signalling mechanism by which obstructive sleep apnoea induces cholinergic basal forebrain degeneration and could thereby increase the risk of developing Alzheimer's disease, as well as providing a rationale for testing a range of possible prophylactic treatment options for people with obstructive sleep apnoea and hypoxia including increased compliance of continuous positive airway pressure therapy. Keywords obstructive sleep apnoea, intermittent hypoxia, basal forebrain, cholinergic neuron, Alzheimer's disease, hypoxia-inducible factor 1alpha, Abbreviations AD: Alzheimer's disease, Aβ: amyloid-beta, APP: amyloid precursor protein, BF: basal forebrain, HIF1α: hypoxia-inducible factor 1 alpha, MPT: mesopontine tegmentum, OSA: obstructive sleep apnoea, p75NTR: p75 neurotrophin receptor, REM: rapid eye movement sleep, UII-SAP: urotensin II-saporin Whole body plethymographyWhole body plethysmography has been used to record respiration during sleep and wake cycles in unrestrained, freely moving mice (Hernandez et al., 2012). The mice were placed in a plethysmograph chamber (Buxco FinePointe Series WBP, DSI) continuously filled with fresh air at room temperature. This approach provides an indirect measure of tidal volume, which is directly proportional to the cyclic chamber pressure signal produced during respiration in a sealed chamber.The mice were first allowed 30 min to acclimatize to the chamber, after which the recording session preceded for 3h. Arterial oxygen saturationThe arterial oxygen saturation was recorded on unrestrained awake mice either in room air or in the environmental chamber using the MouseOx Plus oximeter (Starr Life Sciences) in accordance with the manufacturer's instructions. Data were collected for at least 30 min and only used when no error code was given. Oxygen saturation levels were then calculated as an average per mouse, and per experimental ...

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Section: Cbf Degeneration Is An Early Ad Feature That Can Drive Othersupporting

confidence: 52%

Section: Cbf Degeneration Is Induced By Cmpt Lesionmentioning

confidence: 99%

Section: Osa Induces Pathological Hallmarks Admentioning

confidence: 99%

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Cholinergic basal forebrain degeneration due to obstructive sleep apnoea increases Alzheimer’s pathology in mice

Qian

Kasas

Milne

et al. 2020

Preprint

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“…However, reanalysis of the published images suggests a decrease in adult cBF neuron number. Indeed, heterozygous NGF −/+ mice show a reduced number and size of adult cBF neurons, as well as deficits in memory updating in a Morris water maze reversal learning task [148], a phenotype that is highly reminiscent of MS cBF-lesioned [149] and p75 exonIII−/− mice [136], but is not seen in TrkA-deficient mice (see above). Nestin-cre driven conditional NGF −/− mice, have a 30% loss of cBF neurons, reduced ChAT expression in axons (although not as severe as that in TrkA −/− mice), and a reduced number of nerve terminals in the hippocampus and frontal cortex [144].…”

Section: The Role Of Ngf In Cbf Functionmentioning

confidence: 99%

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

et al. 2019

Self Cite

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Cholinergic basal forebrain (cBF) neurons are defined by their expression of the p75 neurotrophin receptor (p75NTR) and tropomyosin-related kinase (Trk) neurotrophin receptors in addition to cholinergic markers. It is known that the neurotrophins, particularly nerve growth factor (NGF), mediate cholinergic neuronal development and maintenance. However, the role of neurotrophin signalling in regulating adult cBF function is less clear, although in dementia, trophic signalling is reduced and p75NTR mediates neurodegeneration of cBF neurons. Here we review the current understanding of how cBF neurons are regulated by neurotrophins which activate p75NTR and TrkA, B or C to influence the critical role that these neurons play in normal cortical function, particularly higher order cognition. Specifically, we describe the current evidence that neurotrophins regulate the development of basal forebrain neurons and their role in maintaining and modifying mature basal forebrain synaptic and cortical microcircuit connectivity. Understanding the role neurotrophin signalling plays in regulating the precision of cholinergic connectivity will contribute to the understanding of normal cognitive processes and will likely provide additional ideas for designing improved therapies for the treatment of neurological disease in which cholinergic dysfunction has been demonstrated.

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“…The cholinergic inputs to the hippocampus originate primarily from the medial septum and diagonal band of Broca in the basal forebrain (Frotscher & Leranth, ; Mesulam, Mufson, Levey, & Wainer, ; Woolf, ). Damage to the cholinergic system in the basal forebrain is accompanied by memory and cognitive impairment (Laursen, Mork, Plath, Kristiansen, & Bastlund, ; Turnbull, Boskovic, & Coulson, ) and increased risk for Alzheimer's disease (Grothe et al, ; Teipel et al, ). Especially relevant to the current study, is the finding that cholinergic activity in the hippocampus changes after noise exposures (Azman, Zakaria, Abdul Aziz, & Othman, ; Lai, ; Lai, Carino, & Wen, ; Sembulingam, Sembulingam, & Namasivayam, ) and stress induction (Mark, Rada, & Shors, ), raising the question of whether cholinergic innervation in the hippocampus is persistently affected by noise exposure and/or associated with tinnitus.…”

Section: Introductionmentioning

confidence: 99%

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs

Zhang

Martel

et al. 2018

Hippocampus

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Here, we investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for 2 hr and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap‐prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude‐intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed 2‐weeks following noise‐exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20–60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus‐specific changes were particularly prominent in hippocampal synapse‐rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. The robust changes in VAChT labeling in the hippocampus 2 weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus‐specific changes occurred in synapse‐rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus.

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Acute Down-regulation of BDNF Signaling Does Not Replicate Exacerbated Amyloid-β Levels and Cognitive Impairment Induced by Cholinergic Basal Forebrain Lesion

Cited by 18 publications

References 54 publications

Cholinergic basal forebrain degeneration due to obstructive sleep apnoea increases Alzheimer’s pathology in mice

Cholinergic basal forebrain degeneration due to obstructive sleep apnoea increases Alzheimer’s pathology in mice

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs

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