7B2 chaperone knockout in APP model mice results in reduced plaque burden

Abstract

Impairment of neuronal proteostasis is a hallmark of Alzheimer’s and other neurodegenerative diseases. However, the underlying molecular mechanisms leading to pathogenic protein aggregation, and the role of secretory chaperone proteins in this process, are poorly understood. We have previously shown that the neural-and endocrine-specific secretory chaperone 7B2 potently blocks in vitro fibrillation of Aβ42. To determine whether 7B2 can function as a chaperone in vivo, we measured plaque formation and performed behavioral assays in 7B2-deficient mice in an hAPPswe/PS1dE9 Alzheimer’s model mouse background. Surprisingly, immunocytochemical analysis of cortical levels of thioflavin S- and Aβ-reactive plaques showed that APP mice with a partial or complete lack of 7B2 expression exhibited a significantly lower number and burden of thioflavin S-reactive, as well as Aβ-immunoreactive, plaques. However, 7B2 knockout did not affect total brain levels of either soluble or insoluble Aβ. While hAPP model mice performed poorly in the Morris water maze, their brain 7B2 levels did not impact performance. Since 7B2 loss reduced amyloid plaque burden, we conclude that brain 7B2 can impact Aβ disposition in a manner that facilitates plaque formation. These results are reminiscent of prior findings in hAPP model mice lacking the ubiquitous secretory chaperone clusterin.

Secreted Chaperones in Neurodegeneration

“…Support for this mechanism has been presented for clusterin, BRICHOS proteins, and cytoplasmic sHsps ( Rohne et al, 2016 ; Chen et al, 2017 ; Mogk et al, 2019 ) and recent work shows similar properties for GRN-C ( Bhopatkar et al, 2020 ) and for proSAAS ( Peinado et al, 2020 ). In addition, the finding of reduced plaque number in AD model mice lacking 7B2 expression ( Jarvela et al, 2018 ) or clusterin ( DeMattos et al, 2002 ; Wojtas et al, 2017 ) suggests possible roles for 7B2 and clusterin in sequestration events ( Figure 1 , right panel).…”

“…However, among AD patients, contradicting studies have reported either a slight increase ( Winsky-Sommerer et al, 2003 ) or no change ( Iguchi et al, 1987a ) in 7B2 levels. APP transgenic mouse brains also do not show alterations in 7B2 levels, indicating that 7B2 is not upregulated during the course of disease ( Jarvela et al, 2018 ). Majerova et al (2017) showed increased levels of CSF 7B2 in proteomic studies of a tauopathy transgenic rat model of AD.…”

“…Paradoxically, APP model mice lacking 7B2 expression (by crossing with 7B2 knockout mice) exhibit a reduction rather than an increase in Abeta plaques ( Jarvela et al, 2018 ). 7B2 null APP model mice also do not exhibit alterations in soluble Abeta, cognition, or memory compared to similar mice expressing 7B2 ( Jarvela et al, 2018 ).…”

“…Paradoxically, APP model mice lacking 7B2 expression (by crossing with 7B2 knockout mice) exhibit a reduction rather than an increase in Abeta plaques ( Jarvela et al, 2018 ). 7B2 null APP model mice also do not exhibit alterations in soluble Abeta, cognition, or memory compared to similar mice expressing 7B2 ( Jarvela et al, 2018 ). These results are reminiscent of similar paradoxical results obtained in various crosses of clusterin knockout mice with APP model mice ( DeMattos et al, 2002 ; Wojtas et al, 2017 ; Oh et al, 2019 ) which were attributed to the dominance of clearance effects rather than aggregate formation ( Wojtas et al, 2017 ).…”

Short-Term and Long-Term Sensitization Differentially Alters the Composition of an Anterograde Transport Complex inAplysia

“…For example, highly conserved multifunctional 14-3-3 proteins ( Cornell and Toyo-oka, 2017 ) complement protein C1q ( Benoit and Tenner, 2011 ), essentially participating in neural development and neuroprotection. 7B2 precursor ( Jarvela et al, 2018 ), cathepsin B ( Hook et al, 2020 ), and heat shock protein 70 ( Turturici et al, 2011 ) were detected as ApKHC1 cargo is involved in Parkinson’s disease, Alzheimer’s disease, polyglutamine diseases, and amyotrophic lateral sclerosis. Therefore, the present study validates the synaptic mechanics as well as the cellular significance of kinesin motor protein in directional intracellular transport in response to learning-induced memory formation.…”