BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology

Peters, Finn; Salihoglu, Hazal; Rodrigues, Eva Ferreira; Herzog, Étienne; Blume, Tanja; Filser, Severin; Dorostkar, Mario M.; Shimshek, Derya R.; Brose, Nils; Neumann, Ulf; Herms, Jochen

doi:10.1007/s00401-017-1804-9

Cited by 76 publications

(83 citation statements)

References 89 publications

(127 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We addressed the potential reason for the differential effect of tau deletion at different stages of Ab deposition. Interestingly, our data indicate that tau deletion effectively prevented the formation of satellite plaques, which are known to frequently form close to preexisting plaques (McCarter et al, 2013;Peters et al, 2018). Satellite plaque formation might result from enrichment of BACE1 and APP (Zhao et al, 2007) and thus potentiated Ab production (Sadleir et al, 2016) in plaque-associated axonal dystrophies.…”

Section: Discussionmentioning

confidence: 71%

Tau deletion reduces plaque‐associated BACE 1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease

et al. 2019

Self Cite

View full text Add to dashboard Cite

In Alzheimer's disease, BACE1 protease initiates the amyloidogenic processing of amyloid precursor protein (APP) that eventually results in synthesis of β‐amyloid (Aβ) peptide. Aβ deposition in turn causes accumulation of BACE1 in plaque‐associated dystrophic neurites, thereby potentiating progressive Aβ deposition once initiated. Since systemic pharmacological BACE inhibition causes adverse effects in humans, it is important to identify strategies that specifically normalize overt BACE1 activity around plaques. The microtubule‐associated protein tau regulates axonal transport of proteins, and tau deletion rescues Aβ‐induced transport deficits in vitro. In the current study, long‐term in vivo two‐photon microscopy and immunohistochemistry were performed in tau‐deficient APPPS1 mice. Tau deletion reduced plaque‐associated axonal pathology and BACE1 accumulation without affecting physiological BACE1 expression distant from plaques. Thereby, tau deletion effectively decelerated formation of new plaques and reduced plaque compactness. The data revealed that tau reinforces Aβ deposition, presumably by contributing to accumulation of BACE1 in plaque‐associated dystrophies. Targeting tau‐dependent mechanisms could become a suitable strategy to specifically reduce overt BACE1 activity around plaques, thereby avoiding adverse effects of systemic BACE inhibition.

show abstract

Section: Discussionmentioning

confidence: 71%

Tau deletion reduces plaque‐associated BACE 1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…1a-c). We started our recordings at the age of 4.5 months, which in this mouse model represents the early phase of A plaque deposition 26,27 . To characterize the cell identity of the imaged neurons, we performed post-hoc immunostainings and found that the vast majority (96.4 %) of GCaMP6s expressing cells was in fact excitatory (Suppl.…”

Section: Resultsmentioning

confidence: 99%

“…Fig. 4a, week 0: 39.9µm, week 2: 36.8µm, week 4: 34.9 µm -plaque distance decreases as plaques grow over time 27,30,31 ), we divided neurons into close (<= 40 µm form the plaque border) and distant (> 40µm from plaque border) from the nearest plaque, respectively (of note, the effect is also true for other cut offs, such as 20, 60 or 80 µm). The fraction of highly or rarely active neurons did not differ significantly between close and distant neurons at the level of individual experiments (Suppl.…”

Section: Emergence and Fate Of Highly Active Cellsmentioning

confidence: 99%

Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease

Korzhova

Marinković

Goltstein

et al. 2019

Preprint

View full text Add to dashboard Cite

Alzheimer's disease (AD) is associated with aberrant neuronal activity levels. How those activity alterations emerge and how stable they are over time in vivo, however, remains elusive to date. To address these questions we chronically recorded the activity from identified neurons in cortex of awake APPPS1 transgenic mice and their non-transgenic littermates over the course of 4 weeks by means of calcium imaging. Surprisingly, aberrant neuronal activity was very stable over time. Moreover, we identified a slow progressive gain of activity of former intermediately active neurons as the main source of new highly active neurons. Interestingly, fluctuations in neuronal activity were independent from amyloid plaque proximity, but aberrant activity levels were more likely to persist close to plaques. These results support the notion that neuronal network pathology observed in AD patients is the consequence of stable single cell aberrant neuronal activity, a finding of potential therapeutic relevance.

show abstract

“…Acetylcholinesterase inhibitors are efficacious in improving cognitive function of mild‐to‐moderate AD (Gault et al, ). And pharmacological β‐amyloid precursor cleavage enzyme inhibition has found slow progressive β‐amyloid deposition and associated synaptic pathology in a transgenic AD model (Peters et al, ). These may imply that glucuronidated curcumin may have little effect on cognition.…”

Section: Discussionmentioning

confidence: 99%

Curcumin intervention for cognitive function in different types of people: A systematic review and meta‐analysis

Zhu

Mei

Zeng-guo

et al. 2018

Phytotherapy Research

View full text Add to dashboard Cite

Curcumin is a polyphenolic natural compound with diverse and attractive biological activities, which may prevent or ameliorate pathological processes underlying age‐related cognitive decline, dementia, or mood disorders. However, clinical trials and animal studies have yielded conflicting conclusions regarding its effectiveness for cognition in different individuals. The aim of this review is to meta‐analytically assess the effectiveness of curcumin for cognitive function in different types of people. A preliminary search on PubMed, Embase, Web of Science, ClinicalTrials.gov, Cochrane Library, Chinese National Knowledge Infrastructure, and Wanfang Data and China Biology Medicine disc was performed to identify randomized controlled trials investigating the effect of curcumin on cognition. Six clinical trials with a total of 289 subjects met inclusion criteria for this review. We used a random‐effects model to calculate the pooled standardized difference of means (SMD). For older adults who received curcumin, scores on measures of cognitive function (SMD = 0.33, 95% confidence interval [CI] [0.05, 0.62]; p = 0.02), occurrence of adverse events (odds ratio [OR] = 5.59, 95% CI [0.96, 36.80]; p = 0.05), and measures of depression (SMD = −0.29, 95% CI [0.64, 0.05]; p = 0.09) indicated significant memory improvement. In patients with Alzheimer's disease (AD), scores in measures of cognition status (SMD = −0.90, 95% CI [1.48, −0.32]; p = 0.002) indicated that there was a trend for treated subjects to do worse than placebo‐treated subjects on the Mini‐Mental State Examination. The occurrence of adverse events (OR = 0.87, 95% CI [0.10, 7.51]; p = 0.90) was similar to those who received placebo. Due to insufficient data, it was impossible to provide a narrative account of only the outcomes for schizophrenia. Curcumin appears to be more effective in improving cognitive function in the elderly than in improving symptoms of AD and schizophrenia. Curcumin is also safe and tolerated among these individuals. Because of the small number of studies available, a funnel plot or sensitivity analysis was not possible. Further high‐quality trials with larger sample sizes or bioavailability‐improved curcumin formulations may be considered for reliable assessment.

show abstract

BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology

Cited by 76 publications

References 89 publications

Tau deletion reduces plaque‐associated BACE 1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease

Tau deletion reduces plaque‐associated BACE 1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease

Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease

Curcumin intervention for cognitive function in different types of people: A systematic review and meta‐analysis

Contact Info

Product

Resources

About