BAG-1M co-activates BACE1 transcription through NF-κB and accelerates Aβ production and memory deficit in Alzheimer’s disease mouse model

Abstract Beta-amyloid (Aβ) in the brain is a major factor involved in Alzheimer's disease (AD) that results in severe memory deficit. Our recent studies demonstrate pharmacogenetic differences in the effects of inhibitors of cathepsin B to improve memory and reduce Aβ in different mouse models of AD. The inhibitors improve memory and reduce brain Aβ in mice expressing the wild-type (WT) β-secretase site of human APP, expressed in most AD patients. However, these inhibitors have no effect in mice expressing the rare Swedish (Swe) mutant amyloid precursor protein (APP). Knockout of the cathepsin B decreased brain Aβ in mice expressing WT APP, validating cathepsin B as the target. The specificity of cathepsin B to cleave the WT β-secretase site, but not the Swe mutant site, of APP for Aβ production explains the distinct inhibitor responses in the different AD mouse models. In contrast to cathepsin B, the BACE1 β-secretase prefers to cleave the Swe mutant site. Discussion of BACE1 data in the field indicate that they do not preclude cathepsin B as also being a β-secretase. Cathepsin B and BACE1 could participate jointly as β-secretases. Significantly, the majority of AD patients express WT APP and, therefore, inhibitors of cathepsin B represent candidate drugs for AD.

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Decrease of ERK/MAPK Overactivation in Prefrontal Cortex Reverses Early Memory Deficit in a Mouse Model of Alzheimer's Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-131076 ◽

2014 ◽

Vol 40 (1) ◽

pp. 69-82 ◽

Cited By ~ 39

Author(s):

Mariana Feld ◽

María C. Krawczyk ◽

M. Sol Fustiñana ◽

Mariano G. Blake ◽

Carlos M. Baratti ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Prefrontal Cortex ◽

Mouse Model ◽

Memory Deficit ◽

Erk Mapk ◽

Model Of Alzheimer’S Disease ◽

Early Memory

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CHF5074, a Novel γ-Secretase Modulator, Restores Hippocampal Neurogenesis Potential and Reverses Contextual Memory Deficit in a Transgenic Mouse Model of Alzheimer's Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-2010-1366 ◽

2010 ◽

Vol 20 (1) ◽

pp. 159-173 ◽

Cited By ~ 46

Author(s):

Bruno P. Imbimbo ◽

Luciana Giardino ◽

Sandra Sivilia ◽

Alessandro Giuliani ◽

Marco Gusciglio ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Transgenic Mouse ◽

Transgenic Mouse Model ◽

Memory Deficit ◽

Hippocampal Neurogenesis ◽

Contextual Memory ◽

Model Of Alzheimer’S Disease

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BACE1 SUMOylation increases its stability and escalates the protease activity in Alzheimer’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1800498115 ◽

2018 ◽

Vol 115 (15) ◽

pp. 3954-3959 ◽

Cited By ~ 14

Author(s):

Jian Bao ◽

Min Qin ◽

Yacoubou Abdoul Razak Mahaman ◽

Bin Zhang ◽

Fang Huang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Protease Activity ◽

Senile Plaque ◽

Critical Role ◽

Wild Type ◽

Rate Limiting ◽

Aβ Production ◽

Ad Mouse Model

Amyloid beta (Aβ) is a major pathological marker in Alzheimer’s disease (AD), which is principally regulated by the rate-limiting β-secretase (i.e., BACE1) cleavage of amyloid precursor protein (APP). However, how BACE1 activity is posttranslationally regulated remains incompletely understood. Here, we show that BACE1 is predominantly SUMOylated at K501 residue, which escalates its protease activity and stability and subsequently increases Aβ production, leading to cognitive defect seen in the AD mouse model. Compared with a non-SUMOylated K501R mutant, injection of wild-type BACE1 significantly increases Aβ production and triggers cognitive dysfunction. Furthermore, overexpression of wild-type BACE1, but not non-SUMOylated K501R mutant, facilitates senile plaque formation and aggravates the cognitive deficit seen in the APP/PS1 AD mouse model. Together, our data strongly suggest that K501 SUMOylation on BACE1 plays a critical role in mediating its stability and enzymatic activity.

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