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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: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.

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.

Similar Datasets

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