Correction: Mild Oxidative Stress Induces Redistribution of BACE1 in Non-Apoptotic Conditions and Promotes the Amyloidogenic Processing of Alzheimer’s Disease Amyloid Precursor Protein

AbstractDamage to axonal transport is an early pathogenic event in Alzheimer’s disease. The amyloid precursor protein (APP) is a key axonal transport cargo since disruption to APP transport promotes amyloidogenic processing of APP. Moreover, altered APP processing itself disrupts axonal transport. The mechanisms that regulate axonal transport of APP are therefore directly relevant to Alzheimer’s disease pathogenesis. APP is transported anterogradely through axons on kinesin-1 motors and one route for this transport involves calsyntenin-1, a type-1 membrane spanning protein that acts as a direct ligand for kinesin-1 light chains (KLCs). Thus, loss of calsyntenin-1 disrupts APP axonal transport and promotes amyloidogenic processing of APP. Phosphorylation of KLC1 on serine-460 has been shown to reduce anterograde axonal transport of calsyntenin-1 by inhibiting the KLC1-calsyntenin-1 interaction. Here we demonstrate that in Alzheimer’s disease frontal cortex, KLC1 levels are reduced and the relative levels of KLC1 serine-460 phosphorylation are increased; these changes occur relatively early in the disease process. We also show that a KLC1 serine-460 phosphomimetic mutant inhibits axonal transport of APP in both mammalian neurons in culture and in Drosophila neurons in vivo. Finally, we demonstrate that expression of the KLC1 serine-460 phosphomimetic mutant promotes amyloidogenic processing of APP. Together, these results suggest that increased KLC1 serine-460 phosphorylation contributes to Alzheimer’s disease.

Download Full-text

Amyloidogenic processing of Alzheimer’s disease β-amyloid precursor protein induces cellular iron retention

Molecular Psychiatry ◽

10.1038/s41380-020-0762-0 ◽

2020 ◽

Vol 25 (9) ◽

pp. 1958-1966 ◽

Cited By ~ 6

Author(s):

Andrew Tsatsanis ◽

Bruce X. Wong ◽

Adam P. Gunn ◽

Scott Ayton ◽

Ashley I. Bush ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Precursor Protein ◽

Cellular Iron ◽

Amyloidogenic Processing ◽

Iron Retention ◽

Β Amyloid

Download Full-text

HIPPOCAMPAL ASTROCYTES AND ALZHEIMER’S DISEASE

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2014.8 ◽

2014 ◽

pp. 1-5

Author(s):

J. Young

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fatty Acid ◽

Amyloid Precursor Protein ◽

Precursor Protein ◽

Fatty Acid Binding ◽

Age Related ◽

Mature Brain ◽

Hippocampal Astrocytes

Considerable progress has been made in elucidating the molecules involved in the pathology of Alzheimer's disease (AD). However, it is still uncertain why the hippocampus is the focus of this pathology, since these molecules (amyloid precursor protein, beta secretase, apolipoprotein E) are not more abundant within the hippocampus than in other, undamaged brain areas. Several unique features of the hippocampus may make it more vulnerable to this age-related pathology. These include 1) a specialized metabolism that enhances damaging effects of oxidative stress, 2) a capacity for neurogenesis, and 3) specializations in mitochondrial and metal homeostasis. The thesis of this paper is that an unusual subset of hippocampal astrocytes makes a fundamental contribution to all three of these hippocampal features and allows different and seemingly conflicting risk factors for AD to be viewed in a unified manner. These astrocytes participate in neurogenesis, produce fatty acid binding protein 7, unlike most astrocytes in the mature brain, and undergo an age-related mitochondrial degeneration. Degeneration of astrocyte mitochondria appears due to oxidative stress arising from fatty acid metabolism. This mitochondrial degeneration produces intracellular deposits of iron and copper, metals that have been shown to harmfully interact with cleavage products of amyloid precursor protein. Pharmacological and dietary manipulations that protect these astrocytes from age-related oxidative stress may prove to be useful strategies in combatting the progression of AD.

Download Full-text

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.

Download Full-text

Stability analysis of the ODE model representation of amyloidogenic processing in Alzheimer's disease in the presence of SORLA

Molecular BioSystems ◽

10.1039/c5mb00741k ◽

2016 ◽

Vol 12 (5) ◽

pp. 1468-1477 ◽

Cited By ~ 3

Author(s):

Jan Harold M. Alcantara ◽

Angelyn R. Lao ◽

Leonor A. Ruivivar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stability Analysis ◽

Amyloid Precursor Protein ◽

Model Representation ◽

Precursor Protein ◽

Cellular Process ◽

Ode Model ◽

Aβ Peptides ◽

Amyloidogenic Processing

The proteolytic breakdown of the amyloid precursor protein (APP) by secretases is a complex cellular process that results in the formation of neurotoxic Aβ peptides, causative of neurodegeneration in Alzheimer's disease (AD).

Download Full-text

Chronic Administration of Anti-Stroke Herbal Medicine TongLuoJiuNao Reduces Amyloidogenic Processing of Amyloid Precursor Protein in a Mouse Model of Alzheimer’s Disease

PLoS ONE ◽

10.1371/journal.pone.0058181 ◽

2013 ◽

Vol 8 (3) ◽

pp. e58181 ◽

Cited By ~ 14

Author(s):

Ping He ◽

Pengtao Li ◽

Qian Hua ◽

Yuan Liu ◽

Matthias Staufenbiel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Herbal Medicine ◽

Mouse Model ◽

Amyloid Precursor Protein ◽

Chronic Administration ◽

Precursor Protein ◽

Amyloidogenic Processing ◽

Model Of Alzheimer’S Disease

Download Full-text

Memapsin 2, a drug target for Alzheimer's disease

Biochemical Society Symposium ◽

10.1042/bss0700213 ◽

2003 ◽

Vol 70 ◽

pp. 213-220 ◽

Cited By ~ 1

Author(s):

Gerald Koelsch ◽

Robert T. Turner ◽

Lin Hong ◽

Arun K. Ghosh ◽

Jordan Tang

Keyword(s):

Crystal Structure ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transition State ◽

Amyloid Precursor Protein ◽

Therapeutic Target ◽

Drug Target ◽

Aspartic Protease ◽

Precursor Protein ◽

Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

Download Full-text