scholarly journals APP-C31 Is an Intracellular Promoter of Amyloid-Beta Aggregation and Toxicity

2021 ◽  
Author(s):  
Eunju Nam ◽  
Jiyong Park ◽  
Yuxi Lin ◽  
Hyunsu Do ◽  
Jinju Han ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Conformational Transition ◽  
Precursor Protein ◽  
Major Contributor ◽  
Intracellular Level ◽  
Self Recognition ◽  
Human Neurons ◽  
The Brain

<p>Intracellular <i>C</i>-terminal cleavage of the amyloid precursor protein (APP) is elevated in the brain of Alzheimer’s disease (AD). Emerging evidence proposes a pathological relationship between the production of a <i>C</i>-terminal APP fragment, called APP-C31, and the toxicity induced by amyloid-beta (Abeta) that is a major contributor towards AD; however, the interaction between the two peptides and the consequent impact of APP-C31 on Abeta-related toxicity were unknown thus far. Here we report the discovery that APP-C31 facilitates the aggregation of Abeta and aggravates its toxicity at the intracellular level, with escalating neurodegeneration. APP-C31 forms a hetero-dimer with Abeta through the contacts onto the <i>N</i>-terminal and self-recognition regions of Abeta and induces its conformational transition accelerating amyloid fibrillization. APP-C31 promotes the perinuclear and intranuclear deposition of enlarged Abeta aggregates and, consequently, damages the nucleus leading to apoptosis. Abeta-induced degeneration of neurites in human neurons is also intensified by APP-C31. Our studies demonstrate a new function of APP-C31 as an intracellular factor of the proteopathy found in AD.</p>

scholarly journals APP-C31 Is an Intracellular Promoter of Amyloid-Beta Aggregation and Toxicity

2021 ◽  
Author(s):  
Eunju Nam ◽  
Jiyong Park ◽  
Yuxi Lin ◽  
Hyunsu Do ◽  
Jinju Han ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Conformational Transition ◽  
Precursor Protein ◽  
Major Contributor ◽  
Intracellular Level ◽  
Self Recognition ◽  
Human Neurons ◽  
The Brain

<p>Intracellular <i>C</i>-terminal cleavage of the amyloid precursor protein (APP) is elevated in the brain of Alzheimer’s disease (AD). Emerging evidence proposes a pathological relationship between the production of a <i>C</i>-terminal APP fragment, called APP-C31, and the toxicity induced by amyloid-beta (Abeta) that is a major contributor towards AD; however, the interaction between the two peptides and the consequent impact of APP-C31 on Abeta-related toxicity were unknown thus far. Here we report the discovery that APP-C31 facilitates the aggregation of Abeta and aggravates its toxicity at the intracellular level, with escalating neurodegeneration. APP-C31 forms a hetero-dimer with Abeta through the contacts onto the <i>N</i>-terminal and self-recognition regions of Abeta and induces its conformational transition accelerating amyloid fibrillization. APP-C31 promotes the perinuclear and intranuclear deposition of enlarged Abeta aggregates and, consequently, damages the nucleus leading to apoptosis. Abeta-induced degeneration of neurites in human neurons is also intensified by APP-C31. Our studies demonstrate a new function of APP-C31 as an intracellular factor of the proteopathy found in AD.</p>

scholarly journals SPON1 Can Reduce Amyloid Beta and Reverse Cognitive Impairment and Memory Dysfunction in Alzheimer’s Disease Mouse Model

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1275
Author(s):  
Soo Yong Park ◽  
Joo Yeong Kang ◽  
Taehee Lee ◽  
Donggyu Nam ◽  
Chang-Jin Jeon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Physiological Activity ◽  
Precursor Protein ◽  
Age Related

Alzheimer’s disease (AD) is a complex, age-related neurodegenerative disease that is the most common form of dementia. However, the cure for AD has not yet been founded. The accumulation of amyloid beta (Aβ) is considered to be a hallmark of AD. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as beta secretase is the initiating enzyme in the amyloidogenic pathway. Blocking BACE1 could reduce the amount of Aβ, but this would also prohibit the other functions of BACE1 in brain physiological activity. SPONDIN1 (SPON1) is known to bind to the BACE1 binding site of the amyloid precursor protein (APP) and blocks the initiating amyloidogenesis. Here, we show the effect of SPON1 in Aβ reduction in vitro in neural cells and in an in vivo AD mouse model. We engineered mouse induced neural stem cells (iNSCs) to express Spon1. iNSCs harboring mouse Spon1 secreted SPON1 protein and reduced the quantity of Aβ when co-cultured with Aβ-secreting Neuro 2a cells. The human SPON1 gene itself also reduced Aβ in HEK 293T cells expressing the human APP transgene with AD-linked mutations through lentiviral-mediated delivery. We also demonstrated that injecting SPON1 reduced the amount of Aβ and ameliorated cognitive dysfunction and memory impairment in 5xFAD mice expressing human APP and PSEN1 transgenes with five AD-linked mutations.

The β-Secretase Enzyme BACE1: A Biochemical Enigma for Alzheimer’s Disease

2020 ◽  
Vol 19 (3) ◽  
pp. 184-194
Author(s):  
Hirak Shah ◽  
Ashish Patel ◽  
Vruti Parikh ◽  
Afzal Nagani ◽  
Bhargav Bhimani ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Small Molecule ◽  
Normal Function ◽  
Precursor Protein ◽  
Voltage Gated ◽  
Small Series ◽  
The Brain ◽  
Translational Level

Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) is a rational target in Alzheimer’s Disease (AD) drug development due to its role in amyloidogenic cleavage of Amyloid Precursor Protein (APP) in generating Amyloid &#946; (A&#946;). This &#946;-secretase cleaves not only Amyloid Precursor Protein (APP) and its homologues, but also small series of substrates including neuregulin and &#946; subunit of voltage-gated sodium channel that play a very important role in the development and normal function of the brain. Moreover, BACE1 is modulated at the post-translational level by several factors that are associated with both physiological and pathological functions. Since the discovery of BACE1 over a decade ago, medicinal chemistry and pharmacokinetics of BACE1 small molecule inhibitors have proven challenging for the treatment of Alzheimer’s disease.

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