Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease

Haberman, Rebecca P.; Branch, Audrey; Gallagher, Michela

doi:10.1007/s13311-017-0541-z

Cited by 81 publications

(71 citation statements)

References 158 publications

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“…Our findings have important clinical implications: Knowledge of future tau spread can be critical for predicting clinical disease progression, since the level of tau is the strongest predictor of cognitive impairment and cognitive decline in AD 36,37 . Here, blocking tau spread by targeting neural activity related mechanisms of tau spread could be a promising target for attenuating AD progression 21 , especially in view of the limited clinical efficacy of anti-amyloid trials 38,39 .…”

Section: Discussionmentioning

confidence: 99%

“…However, whether functional connectivity between regions is associated with future tau accumulation rates in connected brain regions in living AD patients is unknown. Understanding the role of functional connectivity in the development and spread of tau pathology is of major clinical importance, paving the way towards targeting neural activity related mechanisms of tau pathology to halt clinical AD progression 21 .…”

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confidence: 99%

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Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

2020

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In Alzheimer's diseases (AD), tau pathology is strongly associated with cognitive decline. Preclinical evidence suggests that tau spreads across connected neurons in an activitydependent manner. Supporting this, cross-sectional AD studies show that tau deposition patterns resemble functional brain networks. However, whether higher functional connectivity is associated with higher rates of tau accumulation is unclear. Here, we combine resting-state fMRI with longitudinal tau-PET in two independent samples including 53 (ADNI) and 41 (BioFINDER) amyloid-biomarker defined AD subjects and 28 (ADNI) vs. 16 (Bio-FINDER) amyloid-negative healthy controls. In both samples, AD subjects show faster tau accumulation than controls. Second, in AD, higher fMRI-assessed connectivity between 400 regions of interest (ROIs) is associated with correlated tau-PET accumulation in corresponding ROIs. Third, we show that a model including baseline connectivity and tau-PET is associated with future tau-PET accumulation. Together, connectivity is associated with tau spread in AD, supporting the view of transneuronal tau propagation.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

2020

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“…Based on the finding that BBB dysfunction and TGFβ signaling causes hyperexcitability after head injury (22,24,(26)(27)(28)39), we hypothesized that similar hyperexcitability may be triggered by BBB decline and contribute to cognitive impairment in aging mice. Indeed, hippocampal hyperexcitability is an early biomarker of mild cognitive impairment in humans that precedes progression to AD (42,43), and is also an early marker of disease progression in rodent AD models (44,45). Thus, we used the pentylenetetrazol (PTZ) seizure assay to investigate the time course for onset and progression of hyperexcitability in aging mice.…”

Section: Network Hyperexcitability In Aged Micementioning

confidence: 99%

Blood-brain barrier dysfunction in aging induces hyper-activation of TGF-beta signaling and chronic yet reversible neural dysfunction

Senatorov

Friedman

Milikovsky

et al. 2019

Preprint

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Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-anddysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the lifespan. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology. Specifically, infusion of the serum protein albumin into the young brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors, or pharmacological inhibition of TGFβ signaling, reversed these symptomatic outcomes in aged mice. Finally, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging, and demonstrates that the aging brain may retain considerable latent capacity which can be revitalized by therapeutic inhibition of TGFβ signaling. cm or less), and percentage of time at the novel object was quantified as (duration investigating novel object) / (total duration investigating all three objects). The set objects were chosen from common items such as lab bottles, pipette boxes, cups (placed open-side down), etc., that were of similar dimensions but varied in shape, color, and material. The sequence and position of objects used across trials was identical for all mice.

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“…Although seizures were previously thought to be secondary to AD progression, aberrant activity and/or seizures may directly contribute to cognitive deficits early in the disease [7]. However, there are currently no available disease-modifying therapies, and the failure of several recent pathology-based strategies has highlighted the urgent need for novel effective therapeutic targets [8].…”

Section: Introductionmentioning

confidence: 99%

Exercise-Induced Cognitive Improvement Is Associated with Sodium Channel-Mediated Excitability in APP/PS1 Mice

et al. 2020

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Elevated brain activation, or hyperexcitability, induces cognitive impairment and confers an increased risk of Alzheimer's disease (AD). Blocking the overexcitation of the neural network may be a promising new strategy to prevent, halt, and even reverse this condition. Physical exercise has been shown to be an effective cognitive enhancer that reduces the risk of AD in elderly individuals, but the underlying mechanisms are far from being fully understood. We explored whether long-term treadmill exercise attenuates amyloid precursor protein (APP)/presenilin-1 (PS1) mutation-induced aberrant network activity and thus improves cognition by altering the numbers and/or distribution of voltage-gated sodium channels (Nav) in transgenic mice. APP/PS1 mice aged 2, 3.5, 5, 6.5, 8, and 9 months underwent treadmill exercise with different durations or at different stages of AD. The alterations in memory, electroencephalogram (EEG) recordings, and expression levels and distributions of Nav functional members (Nav1.1α, Nav1.2, Nav1.6, and Navβ2) were evaluated. The results revealed that treadmill exercise with 12and 24-week durations 1) induced significant improvement in novel object recognition (NOR) memory and Morris water maze (MWM) spatial memory; 2) partially reduced abnormal spike activity; and 3) redressed the disturbed cellular distribution of Nav1.1α, aberrant Navβ2 cleavage augmentation, and Nav1.6 upregulation. Additionally, APP/PS1 mice in the 24-week exercise group showed better performance in the NOR task and a large decrease in Nav1.6 expression, which was close to the wild-type level. This study suggests that exercise improves cognition and neural activity by altering the numbers and distribution of hippocampal Nav in APP/PS1 mice. Long-term treadmill exercise, for about 24 weeks, starting in the preclinical stage, is a promising therapeutic strategy for preventing AD and halting its progress.

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Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease

Cited by 81 publications

References 158 publications

Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

Blood-brain barrier dysfunction in aging induces hyper-activation of TGF-beta signaling and chronic yet reversible neural dysfunction

Exercise-Induced Cognitive Improvement Is Associated with Sodium Channel-Mediated Excitability in APP/PS1 Mice

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