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Tau deletion reduces plaque-associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease.

ABSTRACT: In Alzheimer's disease, BACE1 protease initiates the amyloidogenic processing of amyloid precursor protein (APP) that eventually results in synthesis of ?-amyloid (A?) peptide. A? deposition in turn causes accumulation of BACE1 in plaque-associated dystrophic neurites, thereby potentiating progressive A? 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 A?-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 A? 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.

SUBMITTER: Peters F

PROVIDER: S-EPMC6885735 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Tau deletion reduces plaque-associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease.

Peters Finn F Salihoglu Hazal H Pratsch Katrin K Herzog Etienne E Pigoni Martina M Sgobio Carmelo C Lichtenthaler Stefan F SF Neumann Ulf U Herms Jochen J

The EMBO journal 20191107 23

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 activit ...[more]

PMID: 31701556

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Project description:IntroductionAlzheimer's disease (AD) is characterized by increasing cognitive dysfunction, progressive cerebral amyloid beta (Aβ) deposition, and neurofibrillary tangle aggregation. However, the molecular mechanisms of AD pathologies have not been completely understood. As synaptic glycoprotein neuroplastin 65 (NP65) is related with synaptic plasticity and complex molecular events underlying learning and memory, we hypothesized that NP65 would be involved in cognitive dysfunction and Aβ plaque formation of AD. For this purpose, we examined the role of NP65 in the transgenic amyloid precursor protein (APP)/presenilin 1 (PS1) mouse model of AD.MethodsNeuroplastin 65-knockout (NP65-/-) mice crossed with APP/PS1 mice to get the NP65-deficient APP/PS1 mice. In the present study, a separate cohort of NP65-deficient APP/PS1 mice were used. First, the cognitive behaviors of NP65-deficient APP/PS1 mice were assessed. Then, Aβ plaque burden and Aβ levels in NP65-deficient APP/PS1 mice were measured by immunostaining and western blot as well as ELISA. Thirdly, immunostaining and western blot were used to evaluate the glial response and neuroinflammation. Finally, protein levels of 5-hydroxytryptamin (serotonin) receptor 3A and synaptic proteins and neurons were measured.ResultsWe found that loss of NP65 alleviated the cognitive deficits of APP/PS1 mice. In addition, Aβ plaque burden and Aβ levels were significantly reduced in NP65-deficient APP/PS1 mice compared with control animals. NP65-loss in APP/PS1 mice resulted in a decrease in glial activation and the levels of pro- and anti-inflammatory cytokines (IL-1β, TNF-α, and IL-4) as well as protective matrix YM-1 and Arg-1, but had no effect on microglial phenotype. Moreover, NP65 deficiency significantly reversed the increase in 5-hydroxytryptamine (serotonin) receptor 3A (Htr3A) expression levels in the hippocampus of APP/PS1 mice.DiscussionThese findings identify a previously unrecognized role of NP65 in cognitive deficits and Aβ formation of APP/PS1 mice, and suggest that NP65 may serve as a potential therapeutic target for AD.

Project description:TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of ?-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2ko) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2ko mice, with Trem2-deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2ko females at 6-7 months; but by 12 or 19-22 months of age, it was notably diminished in female and male PS2APP;Trem2ko mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2ko brains, and the A?42:A?40 ratio was elevated. The amount of soluble, fibrillar A? oligomers also increased in PS2APP;Trem2ko hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2ko mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of Trem2 deficiency than amyloid plaque load, suggesting that the microglial packing of A? into dense plaque is an important neuroprotective activity.SIGNIFICANCE STATEMENT Genetic studies indicate that TREM2 gene mutations confer increased Alzheimer's disease (AD) risk. We studied the effects of Trem2 deletion in the PS2APP mouse AD model, in which overproduction of A? peptide leads to amyloid plaque formation and associated neuritic dystrophy. Interestingly, neuritic dystrophies were intensified in the brains of Trem2-deficient mice, despite these mice displaying reduced plaque accumulation at later ages (12-22 months). Microglial clustering around plaques was impaired, plaques were more diffuse, and the A?42:A?40 ratio and amount of soluble, fibrillar A? oligomers were elevated in Trem2-deficient brains. These results suggest that the Trem2-dependent compaction of A? into dense plaques is a protective microglial activity, limiting the exposure of neurons to toxic A? species.

Project description:A classical early sign of typical Alzheimer's disease is memory decline, which has been linked to the aggregation of tau in the medial temporal lobe. Verbal delayed free recall and recognition tests have consistently probed useful to detect early memory decline, and there is substantial debate on how performance, particularly in recognition tests, is differentially affected through health and disease in older adults. Using in vivo PET-Braak staging, we investigated delayed recall and recognition memory dysfunction across the Alzheimer's disease spectrum. Our cross-sectional study included 144 cognitively unimpaired elderly, 39 amyloid-β+ individuals with mild cognitive impairment and 29 amyloid-β+ Alzheimer's disease patients from the Translational Biomarkers in Aging and Dementia cohort, who underwent [18F]MK6240 tau and [18F]AZD4694 amyloid PET imaging, structural MRI and memory assessments. We applied non-parametric comparisons, correlation analyses, regression models and voxel-wise analyses. In comparison with PET-Braak Stage 0, we found that reduced, but not clinically significant, delayed recall starts at PET-Braak Stage II (adjusted P < 0.0015), and that recognition (adjusted P = 0.011) displayed a significant decline starting at PET-Braak Stage IV. While performance in both delayed recall and recognition related to tau in nearly the same cortical areas, further analyses showed that delayed recall rendered stronger associations in areas of early tau accumulation, whereas recognition displayed stronger correlations in mostly posterior neocortical regions. Our results support the notion that delayed recall and recognition deficits are predominantly associated with tau load in allocortical and neocortical areas, respectively. Overall, delayed recall seems to be more dependent on the integrity of anterior medial temporal lobe structures, while recognition appears to be more affected by tau accumulation in cortices beyond medial temporal regions.

Dataset Information

Tau deletion reduces plaque-associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease.

Publications

Tau deletion reduces plaque-associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease.

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