Protective mutation A673T as a potential gene therapy for most forms of APP Familial Alzheimer’s Disease

AbstractThe accumulation of plaque in the brain leads to the onset and development of Alzheimer’s disease. The Amyloid precursor protein (APP) is usually cut by α-secretase, however an abnormal cleavage profile by β-secretase (BACE1) leads to the accumulation of Aβ peptides, which forms these plaques. Numerous APP gene mutations favor plaque accumulation, causing Familial Alzheimer Disease (FAD). However, a variant of the APP gene (A673T) in Icelanders reduces BACE1 cleavage by 40 %. A library of plasmids containing APP genes with 29 FAD mutations with or without the additional A673T mutation was generated and transfected in neuroblastomas to assess the effect of this mutation on Aβ peptide production. In most cases the production of Aβ peptides was decreased by the co-dominant A673T mutation. The reduction of Aβ peptide concentrations for the London mutation (V717I) even reached the same level as A673T carriers. These results suggest that the insertion of A673T in the APP gene of genetically susceptible FAD patients may prevent the onset of, slow down, or stop the progression of the disease.

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The protective mutation A673T in amyloid precursor protein gene decreases Aβ peptides production for 14 forms of Familial Alzheimer’s Disease in SH-SY5Y cells

PLoS ONE ◽

10.1371/journal.pone.0237122 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0237122

Author(s):

Antoine Guyon ◽

Joël Rousseau ◽

Gabriel Lamothe ◽

Jacques P. Tremblay

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Precursor Protein ◽

Amyloid Precursor Protein Gene ◽

Aβ Peptide ◽

Aβ Peptides ◽

Amyloidogenic Processing ◽

Icelandic Population ◽

App Gene

The deposition of Aβ plaques in the brain leads to the onset and development of Alzheimer’s disease. The Amyloid precursor protein (APP) is cleaved by α-secretase (non-amyloidogenic processing of APP), however increased cleavage by β-secretase (BACE1) leads to the accumulation of Aβ peptides, which forms plaques. APP mutations mapping to exons 16 and 17 favor plaque accumulation and cause Familial Alzheimer Disease (FAD). However, a variant of the APP gene (A673T) originally found in an Icelandic population reduces BACE1 cleavage by 40%. A series of plasmids containing the APP gene, each with one of 29 different FAD mutations mapping to exon 16 and exon 17 was created. These plasmids were then replicated with the addition of the A673T mutation. Combined these formed the library of plasmids that was used in this study. The plasmids were transfected in neuroblastomas to assess the effect of this mutation on Aβ peptide production. The production of Aβ peptides was decreased for some FAD mutations due to the presence of the co-dominant A673T mutation. The reduction of Aβ peptide concentrations for the London mutation (V717I) even reached the same level as for A673T control in SH-SY5Y cells. These preliminary results suggest that the insertion of A673T in APP genes containing FAD mutations might confer a clinical benefit in preventing or delaying the onset of some FADs.

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Evaluation of a Possible Role of Stigmatella aurantiaca ACE in Aβ Peptide Degradation: A Molecular Modeling Approach

Journal of Molecular Microbiology and Biotechnology ◽

10.1159/000370114 ◽

2015 ◽

Vol 25 (1) ◽

pp. 26-36 ◽

Cited By ~ 5

Author(s):

Chidambar B. Jalkute ◽

Kailas D. Sonawane

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Three Dimensional ◽

Amyloid Β ◽

Dynamics Simulation ◽

Aβ Peptide ◽

Three Dimensional Model ◽

Aβ Peptides ◽

Simulation Techniques ◽

Stigmatella Aurantiaca

Amyloid-β (Aβ)-degrading enzymes are known to degrade Aβ peptides, a causative agent of Alzheimer's disease. These enzymes are responsible for maintaining Aβ concentration. However, loss of such enzymes or their Aβ-degrading activity because of certain genetic as well as nongenetic reasons initiates the accumulation of Aβ peptides in the human brain. Considering the limitations of the human enzymes in clearing Aβ peptide, the search for microbial enzymes that could cleave Aβ is necessary. Hence, we built a three-dimensional model of angiotensin-converting enzyme (ACE) from <i>Stigmatella aurantiaca</i> using homology modeling technique. Molecular docking and molecular dynamics simulation techniques were used to outline the possible cleavage mechanism of Aβ peptide. These findings suggest that catalytic residue Glu 434 of the model could play a crucial role to degrade Aβ peptide between Asp 7 and Ser 8. Thus, ACE from <i>S. aurantiaca</i> might cleave Aβ peptides similar to human ACE and could be used to design new therapeutic strategies against Alzheimer's disease.

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Identification of PSEN1 and APP Gene Mutations in Korean Patients with Early-Onset Alzheimer's Disease

Journal of Korean Medical Science ◽

10.3346/jkms.2008.23.2.213 ◽

2008 ◽

Vol 23 (2) ◽

pp. 213 ◽

Cited By ~ 17

Author(s):

Hyun-Kyung Park ◽

Duk Lyul Na ◽

Jae-Hong Lee ◽

Jong-Won Kim ◽

Chang-Seok Ki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Gene Mutations ◽

Korean Patients ◽

Early Onset Alzheimer’S Disease ◽

App Gene

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326 Whey proteins for prevention and intervention in Alzheimer’s Disease

Journal of Animal Science ◽

10.1093/jas/skaa278.125 ◽

2020 ◽

Vol 98 (Supplement_4) ◽

pp. 68-69

Author(s):

Louise E Bennett

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Whey Proteins ◽

Memory Loss ◽

Aβ Peptides ◽

Over Expression ◽

Potential Benefits ◽

Individual Potential ◽

The Individual ◽

The Brain

Abstract Alzheimer’s disease, resulting from the over-expression of amyloid precursor protein (APP) and accumulation of plaques comprising the APP-derived amyloid beta (Aβ), is a diagnostic and pathological brain feature of Alzheimer’s disease (AD). For older, predisposed people, accumulation of Aβ plaque in the brain precedes symptoms of memory loss by decades. There is a growing consensus that over-expression of APP may also reflect a defense response against infection, via the antibiotic effects of Aβ, which becomes toxic when Aβ peptides cannot be cleared from the brain. These scenarios permit two possible pathways of potential intervention from whey proteins mediated by lactoferrin and hydrolyzed whey proteins. In particular, the interference of fibril assembly whey-derived peptides can promote opportunity for clearance of aggregating forms of Aβ, while the anti-microbial activity of whey proteins such as lactoferrin have potential to suppress the activity of microbes (and viruses) and collectively manage the progress of AD. This presentation will explain the individual potential benefits of whey peptides and lactoferrin, based on available evidence. More research is required to determine if a synergistic effect might be possible from this therapeutic combination.

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Down-regulation of cyclin D2 in amyloid β toxicity, inflammation, and Alzheimer’s disease

PLoS ONE ◽

10.1371/journal.pone.0259740 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0259740

Author(s):

Grzegorz A. Czapski ◽

Magdalena Cieślik ◽

Emilia Białopiotrowicz ◽

Walter J. Lukiw ◽

Joanna B. Strosznajder

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Aβ Peptide ◽

Cyclin Dependent Kinase ◽

Wild Type ◽

Cyclin D2 ◽

Aβ Peptides ◽

Expression Of Genes ◽

Genes Encoding

In the current study, we analyzed the effects of the systemic inflammatory response (SIR) and amyloid β (Aβ) peptide on the expression of genes encoding cyclins and cyclin-dependent kinase (Cdk) in: (i) PC12 cells overexpressing human beta amyloid precursor protein (βAPP), wild-type (APPwt-PC12), or carrying the Swedish mutantion (APPsw-PC12); (ii) the murine hippocampus during SIR; and (iii) Alzheimer’s disease (AD) brain. In APPwt-PC12 expression of cyclin D2 (cD2) was exclusively reduced, and in APPsw-PC12 cyclins cD2 and also cA1 were down-regulated, but cA2, cB1, cB2, and cE1 were up-regulated. In the SIR cD2, cB2, cE1 were found to be significantly down-regulated and cD3, Cdk5, and Cdk7 were significantly up-regulated. Cyclin cD2 was also found to be down-regulated in AD neocortex and hippocampus. Our novel data indicate that Aβ peptide and inflammation both significantly decreased the expression of cD2, suggesting that Aβ peptides may also contribute to downregulation of cD2 in AD brain.

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Structural biology of Alzheimer's disease

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314093012 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C698-C698

Author(s):

Luke Miles ◽

Gabriela Crespi ◽

Tracy Nero ◽

Michael Parker

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cross Reactivity ◽

Soluble Form ◽

Plaque Burden ◽

Breakdown Product ◽

Pathological Feature ◽

Aβ Peptide ◽

Aβ Peptides ◽

N Terminus

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in humans with age being the biggest risk factor. The mechanisms by which the disease progresses to cognitive decline in the sufferer are complex and not fully elucidated. A defining pathological feature is the deposition of extracellular plaques composed primarily of misfolded amyloid beta (Aβ) peptide: a proteolytic breakdown product of the much larger Amyloid Precursor Protein. While Aβ peptides are the main constituents of amyloid plaques that burden the diseased brain, plaque burden correlates poorly with the severity of the disease. There is accumulating evidence that a prefibrillar or protofibrillar soluble form of Aβ can compromise neuronal functions and trigger cell death. Immunotherapy targeting Abeta is a promising direction in AD research with active and passive immunotherapies shown to lower cerebral Aβ levels and rescue cognitive function in animal models. Anti-Aβ immunotherapies are a significant class of AD therapeutics currently in human clinical trials. We have been examining the molecular basis of antibody engagement of Aβ epitopes to inform the analysis of clinical trial data and to guide the engineering of anti-Aβ antibodies with optimised specificity and affinity. We have determined the structures of three different AD antibodies in complex with Ab peptides: (1) WO2, which recognises the N-terminus of Aβ, (2) Mab 2286, which like the AD immunotherapeutic Ponezumab (Pfizer), shows specificity for the C-terminus of Aβ40 but has no significant cross-reactivity with Aβ42/43, and (3) Bapineuzumab, a humanized antibody developed by Pfizer and Johnson & Johnson which recognises the N-terminus of Aβ but cannot recognize N-terminally modified or truncated Aβ peptides (1). All these studies reveal surprising aspects of Aβ peptide recognition by the antibodies and suggest new avenues for AD antibody development.

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Fluid Candidate Biomarkers for Alzheimer’s Disease: A Precision Medicine Approach

Journal of Personalized Medicine ◽

10.3390/jpm10040221 ◽

2020 ◽

Vol 10 (4) ◽

pp. 221 ◽

Cited By ~ 1

Author(s):

Eleonora Del Prete ◽

Maria Francesca Beatino ◽

Nicole Campese ◽

Linda Giampietri ◽

Gabriele Siciliano ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Misfolding ◽

Plasma Biomarker ◽

Clinical Role ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Aβ Peptides ◽

The Brain

A plethora of dynamic pathophysiological mechanisms underpins highly heterogeneous phenotypes in the field of dementia, particularly in Alzheimer’s disease (AD). In such a faceted scenario, a biomarker-guided approach, through the implementation of specific fluid biomarkers individually reflecting distinct molecular pathways in the brain, may help establish a proper clinical diagnosis, even in its preclinical stages. Recently, ultrasensitive assays may detect different neurodegenerative mechanisms in blood earlier. ß-amyloid (Aß) peptides, phosphorylated-tau (p-tau), and neurofilament light chain (NFL) measured in blood are gaining momentum as candidate biomarkers for AD. P-tau is currently the more convincing plasma biomarker for the diagnostic workup of AD. The clinical role of plasma Aβ peptides should be better elucidated with further studies that also compare the accuracy of the different ultrasensitive techniques. Blood NFL is promising as a proxy of neurodegeneration process tout court. Protein misfolding amplification assays can accurately detect α-synuclein in cerebrospinal fluid (CSF), thus representing advancement in the pathologic stratification of AD. In CSF, neurogranin and YKL-40 are further candidate biomarkers tracking synaptic disruption and neuroinflammation, which are additional key pathophysiological pathways related to AD genesis. Advanced statistical analysis using clinical scores and biomarker data to bring together individuals with AD from large heterogeneous cohorts into consistent clusters may promote the discovery of pathophysiological causes and detection of tailored treatments.

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Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.609073 ◽

2020 ◽

Vol 13 ◽

Author(s):

Madeleine R. Brown ◽

Sheena E. Radford ◽

Eric W. Hewitt

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Fibril ◽

Amyloid Β ◽

Aβ Peptides ◽

Aβ Amyloid ◽

Aβ Fibrils ◽

The Brain

Amyloid plaques are a pathological hallmark of Alzheimer’s disease. The major component of these plaques are highly ordered amyloid fibrils formed by amyloid-β (Aβ) peptides. However, whilst Aβ amyloid fibril assembly has been subjected to detailed and extensive analysis in vitro, these studies may not reproduce how Aβ fibrils assemble in the brain. This is because the brain represents a highly complex and dynamic environment, and in Alzheimer’s disease multiple cofactors may affect the assembly of Aβ fibrils. Moreover, in vivo amyloid plaque formation will reflect the balance between the assembly of Aβ fibrils and their degradation. This review explores the roles of microglia as cofactors in Aβ aggregation and in the clearance of amyloid deposits. In addition, we discuss how infection may be an additional cofactor in Aβ fibril assembly by virtue of the antimicrobial properties of Aβ peptides. Crucially, by understanding the roles of microglia and infection in Aβ amyloid fibril assembly it may be possible to identify new therapeutic targets for Alzheimer’s disease.

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