Gene dosage of the amyloid beta precursor protein in Alzheimer's disease

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.

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Brain-wide atlas of amyloid-beta distribution in transgenic amyloid precursor protein mouse model of Alzheimer’s disease

Frontiers in Neuroinformatics ◽

10.3389/conf.fninf.2013.09.00002 ◽

2013 ◽

Vol 7 ◽

Author(s):

Lillehaug Sveinung ◽

Syverstad Gry ◽

Nilsson Lars ◽

Torp Reidun ◽

Bjaalie Jan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Amyloid Precursor Protein ◽

Amyloid Beta ◽

Beta Distribution ◽

Precursor Protein ◽

Model Of Alzheimer’S Disease ◽

Amyloid Precursor Protein Mouse

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P1-153: DDT EXPOSURE INCREASES LEVELS OF THE AMYLOID PRECURSOR PROTEIN, AMYLOID BETA, AND PROINFLAMMATORY FACTORS: MECHANISTIC LINKS TO ALZHEIMER'S DISEASE RISK

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.708 ◽

2019 ◽

Vol 15 ◽

pp. P295-P295

Author(s):

Aseel Eid ◽

Jason R. Richardson ◽

Charles White ◽

Dwight C. German

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Amyloid Beta ◽

Disease Risk ◽

Precursor Protein ◽

Proinflammatory Factors

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Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signaling

10.1101/585489 ◽

2019 ◽

Author(s):

Claire S. Durrant ◽

Karsten Ruscher ◽

Olivia Sheppard ◽

Michael P. Coleman ◽

Ilknur Özen

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Amyloid Beta ◽

Precursor Protein ◽

Vascular Pathology ◽

Amyloid Precursor Protein Processing ◽

App Processing ◽

Bace1 Inhibition

AbstractAmyloid beta peptides (Aβ) proteins play a key role in vascular pathology in Alzheimer’s Disease (AD) including impairment of the blood brain barrier and aberrant angiogenesis. Although previous work has demonstrated a pro-angiogenic role of Aβ, the exact mechanisms by which amyloid precursor protein (APP) processing and endothelial angiogenic signalling cascades interact in AD remain a largely unsolved problem. Here, we report that increased endothelial sprouting in human-APP transgenic mouse (TgCRND8) tissue is dependent on β-secretase (BACE1) processing of APP. Higher levels of Aβ processing in TgCRND8 tissue coincides with decreased NOTCH3/JAG1 signalling, over-production of endothelial filopodia and increased numbers of vascular pericytes. Using a novel in vitro approach to study sprouting angiogenesis in TgCRND8 organotypic brain slice cultures (OBSCs), we find that BACE1 inhibition normalises excessive endothelial filopodia formation and restores NOTCH3 signalling. These data present the first evidence for the potential of BACE1 inhibition as an effective therapeutic target for aberrant angiogenesis in AD.SignificanceIn this study, we show that targeting amyloid beta processing provides an opportunity to selectively target tip cell filopodia-driven angiogenesis and develop therapeutic targets for vascular dysfunction related to aberrant angiogenesis in AD. Our data provide the first evidence for a safe level of BACE1 inhibition that can normalize excess angiogenesis in AD, without inducing vascular deficits in healthy tissue. Our findings may pave the way for the development of new angiogenesis dependent therapeutic strategies in Alzheimer’s Disease.

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Insight γ-Secretase: Structure, Function and Role in Alzheimer’s Disease

Current Drug Targets ◽

10.2174/1389450121999201230203709 ◽

2020 ◽

Vol 22 ◽

Author(s):

Suvadeep Mal ◽

Udita Malik ◽

Dilipkumar Pal ◽

Abhishek Mishra

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Amyloid Beta ◽

Transmembrane Protein ◽

Precursor Protein ◽

Gamma Secretase ◽

Protein Cleavage ◽

Brain Disorder ◽

Amino Acid Peptide

Abstract:: Neurodegenerative disorders are the state of body results in progressive degeneration leading to death of nerve cells. In this state, a patient gets affected day by day with mental weakness, dementia and ataxia. Alzheimer’s disease (AD) is the most common irreversible neurodegenerative brain disorder mainly affecting people over the age of 65 years. Many researches suggest a fact that the main culprit for AD is the aggregated form of a (39-43) amino acid peptide called amyloid beta. Amyloid beta (Aβ) is generated by the action of beta secretase and gamma secretase on larger glycoprotein. Gamma (γ) secretase is an intra-membrane protease complex which cleaves the single-pass transmembrane protein, cleavage of amyloid precursor protein and Notch. γ-secretase complex contains presenilin, presenilin enhancer-2, anterior pharynx defective-1 and nicastrin. Any mutation in presenilin-1 or the cleavage of amyloid precursor protein by γ-secretase directly or indirectly associated with AD. So, prevention of this enzyme is one of the solutions for AD. In this article, we discuss about γ-secretase complex and its inhibitors that can contribute to the prevention of AD.

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