Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives

1997 ◽  
Vol 77 (4) ◽  
pp. 1081-1132 ◽  
Author(s):  
M. P. Mattson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Amyloid Fibrils ◽  
Neuronal Excitability ◽  
Neuronal Degeneration ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Transport Systems ◽  
Age Related

beta-Amyloid precursor protein (beta-APP), the source of the fibrillogenic amyloid beta-peptide (A beta) that accumulates in the brain of victims of Alzheimer's disease, is a multifunctional protein that is widely expressed in the nervous system. beta-Amyloid precursor protein is axonally transported and accumulates in presynaptic terminals and growth cones. A secreted form of beta-APP (sAPP alpha) is released from neurons in response to electrical activity and may function in modulation of neuronal excitability, synaptic plasticity, neurite outgrowth, synaptogenesis, and cell survival. A signaling pathway involving guanosine 3',5'-cyclic monophosphate is activated by sAPP alpha and modulates the activities of potassium channels, N-methyl-D-aspartate receptors, and the transcription factor NF kappa B. Additional functions of beta-APP may include modulation of cell adhesion and regulation of proliferation of nonneuronal cells. Alternative enzymatic processing of beta-APP liberates A beta, which has a propensity to form amyloid fibrils; A beta can damage and kill neurons and increase their vulnerability to excitotoxicity. The mechanism involves generation of oxyradicals and impairment of membrane transport systems (e.g., ion-motive ATPases and glutamate and glucose transporters). Genetic mutations or age-related metabolic changes may promote neuronal degeneration in Alzheimer's disease by increasing production of A beta and/or decreasing levels of neuroprotective sAPP alpha.

scholarly journals Beta-Amyloid Precursor Protein (βAPP) Processing in Alzheimer’s Disease (AD) and Age-Related Macular Degeneration (AMD)

2014 ◽  
Vol 52 (1) ◽  
pp. 533-544 ◽  
Author(s):  
Yuhai Zhao ◽  
Surjyadipta Bhattacharjee ◽  
Brandon M. Jones ◽  
James M. Hill ◽  
Christian Clement ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Macular Degeneration ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Age Related Macular Degeneration ◽  
Age Related

Understanding the structural requirements of cyclic sulfone hydroxyethylamines as hBACE1 inhibitors against Aβ plaques in Alzheimer's disease: a predictive QSAR approach

RSC Advances ◽  
2016 ◽  
Vol 6 (34) ◽  
pp. 28171-28186 ◽  
Author(s):  
Pravin Ambure ◽  
Kunal Roy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Structural Requirements ◽  
Amyloid Aβ

Beta (β)-site amyloid precursor protein cleaving enzyme 1 (BACE1) is one of the most important targets in Alzheimer's disease (AD), which is responsible for production and accumulation of beta amyloid (Aβ).

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.

scholarly journals Might Fibroblasts from Patients with Alzheimer’s Disease Reflect the Brain Pathology? A Focus on the Increased Phosphorylation of Amyloid Precursor Protein Tyr682 Residue

2021 ◽  
Vol 11 (1) ◽  
pp. 103
Author(s):  
Filomena Iannuzzi ◽  
Vincenza Frisardi ◽  
Lucio Annunziato ◽  
Carmela Matrone
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Neurodegenerative Disorder ◽  
Neuronal Degeneration ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Diagnostic Strategy ◽  
Peripheral Cells ◽  
The Brain

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with no cure and no effective diagnostic criteria. The greatest challenge in effectively treating AD is identifying biomarkers specific for each patient when neurodegenerative processes have not yet begun, an outcome that would allow the design of a personalised therapeutic approach for each patient and the monitoring of the therapeutic response during the treatment. We found that the excessive phosphorylation of the amyloid precursor protein (APP) Tyr682 residue on the APP 682YENPTY687 motif precedes amyloid β accumulation and leads to neuronal degeneration in AD neurons. We proved that Fyn tyrosine kinase elicits APP phosphorylation on Tyr682 residue, and we reported increased levels of APP Tyr682 and Fyn overactivation in AD neurons. Here, we want to contemplate the possibility of using fibroblasts as tools to assess APP Tyr682 phosphorylation in AD patients, thus making the changes in APP Tyr682 phosphorylation levels a potential diagnostic strategy to detect early pathological alterations present in the peripheral cells of AD patients’ AD brains.

scholarly journals β-Secretases, Alzheimer’s Disease, and Down Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Robin L. Webb ◽  
M. Paul Murphy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Amyloid Precursor Protein ◽  
Healthy Aging ◽  
Precursor Protein ◽  
Chromosome 21 ◽  
Rate Limiting Step ◽  
Age Related

Individuals with Down Syndrome (DS), or trisomy 21, develop Alzheimer’s disease (AD) pathology by approximately 40 years of age. Chromosome 21 harbors several genes implicated in AD, including the amyloid precursor protein and one homologue of theβ-site APP cleaving enzyme, BACE2. Processing of the amyloid precursor protein byβ-secretase (BACE) is the rate-limiting step in the production of the pathogenic Aβpeptide. Increased amounts of APP in the DS brain result in increased amounts of Aβand extracellular plaque formation beginning early in life. BACE dysregulation potentially represents an overlapping biological mechanism with sporadic AD and a common therapeutic target. As the lifespan for those with DS continues to increase, age-related concerns such as obesity, depression, and AD are of growing concern. The ability to prevent or delay the progression of neurodegenerative diseases will promote healthy aging and improve quality of life for those with DS.

scholarly journals A Possible Role for Cathepsins D, E, and B in the Processing of beta-amyloid Precursor Protein in Alzheimer's Disease

1997 ◽  
Vol 244 (2) ◽  
pp. 414-425 ◽  
Author(s):  
Elaine A. Mackay ◽  
Anne Ehrhard ◽  
Marc Moniatte ◽  
Chantal Guenet ◽  
Chantal Tardif ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Beta Amyloid ◽  
Precursor Protein

scholarly journals Intensive protein synthesis in neurons and phosphorylation of beta-amyloid precursor protein and tau-protein are triggering factors of neuronal amyloidosis and Alzheimer's disease

2013 ◽  
Vol 59 (2) ◽  
pp. 144-170 ◽  
Author(s):  
A.V. Maltsev ◽  
N.V. Dovidchenko ◽  
V.K. Uteshev ◽  
V.V. Sokolik ◽  
O.M. Shtang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Amyloid Precursor Protein ◽  
Tau Protein ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Tau Proteins ◽  
Neuron Death ◽  
Protective Mechanisms

Recently the studies of Alzheimer’s disease have become particularly actual and have attracted scientists from all over the world to this problem as a result of dissemination of this dangerous disorder. The reason for such pathogenesis is not known, but the final image, for the first time obtained on microscopic brain sections from patients with this disease more than a hundred years ago, is well known to clinicists. This is the deposition of Ab amyloid in the brain tissue of senile plaques and fibrils. Many authors suppose that the deposition of beta-amyloid provokes secondary neuronal changes which are the reason of neuron death. Other authors associate the death of neurons with hyperphosphorylation of tau-proteins which form neurofibrillar coils inside nerve cells and lead to their death. For creation of methods of preclinical diagnostics and effective treatment of Alzheimer’s disease novel knowledge is required on the nature of triggering factors of sporadic isoforms of Alzheimer’s disease, on cause-effect relationships of phosphorylation of amyloid precursor protein with formation of pathogenic beta-amyloids, on the relationship with these factors of hyperphosphorylation of tau-protein and neuron death. In this review we analyze the papers describing the increasing of intensity of biosynthesis in neurons in normal conditions and under the stress, the possibility of development of energetic unbalanced neurons and activation of their protective systems. Phosphorylation and hyperphosphorylation of tau-proteins is also tightly connected with protective mechanisms of cells and with processes of evacuation of phosphates, adenosine mono-phosphates and pyrophosphates from the region of protein synthesis. Upon long and high intensity of protein synthesis the protective mechanisms are overloaded and the complementarity of metabolitic processes is disturbed. This results in dysfunction of neurons, transport collapse, and neuron death.

Sign in / Sign up

Export Citation Format

Share Document