Upregulation of APP endocytosis by neuronal aging drives amyloid-dependent synapse loss

Burrinha, Tatiana; Martinsson, Isak; Gomes, Ricardo A.; Terrasso, Ana Paula; Gouras, Gunnar K.; Almeida, Cláudia G.

doi:10.1242/jcs.255752

Cited by 35 publications

(77 citation statements)

References 159 publications

(233 reference statements)

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“…Furthermore, using typical AD biomarkers (Aβ accumulation, reactive astrocytes, and dystrophic neurons), we did not find close similarities between young AD and aged WT mice. We cannot exclude that in the latter, other changes in astrocytes and microglia as well as subthreshold amount of Aβ or other products of the APP processing may be sufficient to induce the observed network alterations [ 101 , 102 ].…”

Section: Discussionmentioning

confidence: 99%

Accelerated Aging Characterizes the Early Stage of Alzheimer’s Disease

Leparulo

Bisio

Redolfi

et al. 2022

Cells

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For Alzheimer’s disease (AD), aging is the main risk factor, but whether cognitive impairments due to aging resemble early AD deficits is not yet defined. When working with mouse models of AD, the situation is just as complicated, because only a few studies track the progression of the disease at different ages, and most ignore how the aging process affects control mice. In this work, we addressed this problem by comparing the aging process of PS2APP (AD) and wild-type (WT) mice at the level of spontaneous brain electrical activity under anesthesia. Using local field potential recordings, obtained with a linear probe that traverses the posterior parietal cortex and the entire hippocampus, we analyzed how multiple electrical parameters are modified by aging in AD and WT mice. With this approach, we highlighted AD specific features that appear in young AD mice prior to plaque deposition or that are delayed at 12 and 16 months of age. Furthermore, we identified aging characteristics present in WT mice but also occurring prematurely in young AD mice. In short, we found that reduction in the relative power of slow oscillations (SO) and Low/High power imbalance are linked to an AD phenotype at its onset. The loss of SO connectivity and cortico-hippocampal coupling between SO and higher frequencies as well as the increase in UP-state and burst durations are found in young AD and old WT mice. We show evidence that the aging process is accelerated by the mutant PS2 itself and discuss such changes in relation to amyloidosis and gliosis.

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Section: Discussionmentioning

confidence: 99%

Accelerated Aging Characterizes the Early Stage of Alzheimer’s Disease

Leparulo

Bisio

Redolfi

et al. 2022

Cells

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“…Importantly, we observed the same profile in human brain samples, in which we established a positive correlation between APP processing and aging. Considering the previously described accumulation of CTFs (Burrinha et al, 2021) and increased BACE1 activity (Fukumoto et al, 2004) in aged mice, we postulate that APP-derived amyloidogenic fragments accumulate and alter NMDAR function. To test this hypothesis, we used a β-secretase 1 (BACE 1) inhibitor in aged animals to block the APP amyloidogenic processing, which resulted in a decrease in GluN2B synaptic contribution of about 20%, getting closer to the results obtained in adult mice.…”

Section: Discussionmentioning

confidence: 81%

“…The aging impact on APP processing is likely independent of cellular APP levels alterations, which we found unaltered. APP endocytosis was shown to be upregulated in aging, thus favouring APP processing through the amyloidogenic pathway (Burrinha et al, 2021). We therefore blocked APP amyloidogenic processing in aged mice by oral administration of a β-secretase 1 (BACE 1) (BI) inhibitor (LY2811376; 100mg/kg), 12 h prior to patch-clamp recordings ( Figure 4i, j ).…”

Section: Resultsmentioning

confidence: 99%

Age-dependent NMDA receptor function is regulated by the Amyloid Precursor Protein

Rajão‐Saraiva

Temido‐Ferreira

Coelho

et al. 2022

Preprint

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N-methyl-D-aspartate receptors (NMDARs) are critical for the maturation and plasticity of glutamatergic synapses. In the hippocampus, NMDARs mainly contain GluN2A and/or GluN2B regulatory subunits. The amyloid precursor protein (APP) has emerged as a putative regulator of NMDARs, but the impact of this interaction to their function is largely unknown. By combining patch-clamp electrophysiology and molecular approaches, we unravel a dual mechanism by which APP controls GluN2B-NMDARs, depending on the life stage. We show that APP is highly abundant specifically at the postnatal postsynapse. It interacts with GluN2B-NMDARs, controlling its synaptic content and mediated currents, both in infant mice and primary neuronal cultures. Upon aging, the APP amyloidogenic derived C-terminal fragments, rather than APP full length, contribute to aberrant GluN2B-NMDAR currents. Accordingly, we found that the APP processing is increased upon aging, both in mice and human brain, and interfering with this mechanism normalized the aberrant currents. While the first mechanism might be essential for synaptic maturation during development, the latter could contribute to age-related synaptic impairments.

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“…Cell and systems biology studies have reported disturbances in the autophagy and endolysosomal pathways as initial molecular changes in sporadic and familial AD cases, suggesting defects in these pathways underlying AD pathogenesis [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. In line with these results, APP, the amyloid precursor protein, is a transmembrane protein situated in the cell membrane and several organelles, including endosomes and autophagic vesicles, indicating that failures in autophagy endolysosomal activities contribute to the amyloid β accumulation [ 9 , 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 77%

Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease

Espinoza

Grunenwald

Gómez

et al. 2022

Cells

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Alzheimer’s disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicon’s role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid β burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid β burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP/amyloid β secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APP/amyloid β homeostasis, in which neuronal Rubicon is a repressor of APP/amyloid β secretion, defining a new way to target AD and other similar diseases therapeutically.

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Upregulation of APP endocytosis by neuronal aging drives amyloid-dependent synapse loss

Cited by 35 publications

References 159 publications

Accelerated Aging Characterizes the Early Stage of Alzheimer’s Disease

Accelerated Aging Characterizes the Early Stage of Alzheimer’s Disease

Age-dependent NMDA receptor function is regulated by the Amyloid Precursor Protein

Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease

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