A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons

The amyloid precursor protein (APP) is a ubiquitously expressed type 1 transmembrane protein mostly known for serving as a precursor to the amyloid-β peptide (Aβ), a culprit in Alzheimer disease (AD). However, APP also has important physiological functions by being implicated in, for instance, adhesion, signaling, neuronal development and synaptic function. Human APP contains two N-glycosylation sites, at asparagine (N) 467 (N467) and N496. Here, we studied the role of N-glycosylation on APP trafficking and processing by constructing APP-SNAP plasmid vectors for wildtype APP and N-glycosylation site mutants in which N467 or N496 was replaced by glutamine (Q) and expressed these in HEK293T cells. Lack of either of the two N-glycans resulted in a reduction in the size of intracellular APP-SNAP-positive vesicles and a reduction of APP-SNAP in the plasma membrane and lysosomes. Importantly, loss of either of the two N-glycans resulted in elevated levels of intracellular as well as secreted Aβ42. These data suggest that N-glycans have a major impact on trafficking and processing of APP and could play an important role in the development of AD.

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“…Leica TCS SP8 STED 3X with Leica microsystems was used for STED imaging, essentially as described previously ( Yu et al. 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Lack of N-glycosylation increases amyloidogenic processing of the amyloid precursor protein

Tong

Husen

et al. 2022

Glycobiology

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“…However, amyloid plaques can induce synaptic dysfunction and an inflammatory response that ultimately triggers neurodegeneration. In a healthy individual, the non-amyloidogenic pathway predominates, while in a patient with AD, Aβ clearance is lower than its production through the amyloidogenic pathway [ 55 , 56 ].…”

Section: Pathological Mechanismsmentioning

confidence: 99%

Early- and Late-Onset Alzheimer’s Disease: Two Sides of the Same Coin?

Valdez-Gaxiola,

Rosales-Leycegui,

Gaxiola-Rubio

et al. 2024

Diseases

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Early-onset Alzheimer’s disease (EOAD), defined as Alzheimer’s disease onset before 65 years of age, has been significantly less studied than the “classic” late-onset form (LOAD), although EOAD often presents with a more aggressive disease course, caused by variants in the APP, PSEN1, and PSEN2 genes. EOAD has significant differences from LOAD, including encompassing diverse phenotypic manifestations, increased genetic predisposition, and variations in neuropathological burden and distribution. Phenotypically, EOAD can be manifested with non-amnestic variants, sparing the hippocampi with increased tau burden. The aim of this article is to review the different genetic bases, risk factors, pathological mechanisms, and diagnostic approaches between EOAD and LOAD and to suggest steps to further our understanding. The comprehension of the monogenic form of the disease can provide valuable insights that may serve as a roadmap for understanding the common form of the disease.

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“…Yu and coauthors [107] used STED to clarify the pre and postsynaptic subcellular locations of fragments involved in the amyloidogenic pathway in primary neurons with a focus on 42 amino acid-long amyloid-beta peptide (Aβ42) and its immediate substrate AβPP C-terminal fragment (APP-CTF).…”

Section: Super-resolution Imagingmentioning

confidence: 99%

Digging Deeper: Advancements in Visualization of Inhibitory Synapses in Neurodegenerative Disorders

Radulović

Sunkara

Maurer

et al. 2021

IJMS

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Recent research has provided strong evidence that neurodegeneration may develop from an imbalance between synaptic structural components in the brain. Lately, inhibitory synapses communicating via the neurotransmitters GABA or glycine have come to the center of attention. Increasing evidence suggests that imbalance in the structural composition of inhibitory synapses affect deeply the ability of neurons to communicate effectively over synaptic connections. Progressive failure of synaptic plasticity and memory are thus hallmarks of neurodegenerative diseases. In order to prove that structural changes at synapses contribute to neurodegeneration, we need to visualize single-molecule interactions at synaptic sites in an exact spatial and time frame. This visualization has been restricted in terms of spatial and temporal resolution. New developments in electron microscopy and super-resolution microscopy have improved spatial and time resolution tremendously, opening up numerous possibilities. Here we critically review current and recently developed methods for high-resolution visualization of inhibitory synapses in the context of neurodegenerative diseases. We present advantages, strengths, weaknesses, and current limitations for selected methods in research, as well as present a future perspective. A range of new options has become available that will soon help understand the involvement of inhibitory synapses in neurodegenerative disorders.

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A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons

Cited by 7 publications

References 55 publications

Lack of N-glycosylation increases amyloidogenic processing of the amyloid precursor protein

Lack of N-glycosylation increases amyloidogenic processing of the amyloid precursor protein

Early- and Late-Onset Alzheimer’s Disease: Two Sides of the Same Coin?

Digging Deeper: Advancements in Visualization of Inhibitory Synapses in Neurodegenerative Disorders

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