Ion channel formation by N-terminally truncated Aβ (4-42): relevance for the pathogenesis of Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Karkisaval AG
PROVIDER: S-EPMC8132454 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Accumulation of amyloid-? peptides is a dominant feature in the pathogenesis of Alzheimer's disease; however, it is not clear how individual amyloid-? species accumulate and affect other neuropathological and clinical features in the disease. Thus, we compared the accumulation of N-terminally truncated amyloid-? and full-length amyloid-?, depending on disease stage as well as brain area, and determined how these amyloid-? species respectively correlate with clinicopathological features of Alzheimer's disease. To this end, the amounts of amyloid-? species and other proteins related to amyloid-? metabolism or Alzheimer's disease were quantified by enzyme-linked immunosorbent assays (ELISA) or theoretically calculated in 12 brain regions, including neocortical, limbic and subcortical areas from Alzheimer's disease cases (n = 19), neurologically normal elderly without amyloid-? accumulation (normal ageing, n = 13), and neurologically normal elderly with cortical amyloid-? accumulation (pathological ageing, n = 15). We observed that N-terminally truncated amyloid-?42 and full-length amyloid-?42 accumulations distributed differently across disease stages and brain areas, while N-terminally truncated amyloid-?40 and full-length amyloid-?40 accumulation showed an almost identical distribution pattern. Cortical N-terminally truncated amyloid-?42 accumulation was increased in Alzheimer's disease compared to pathological ageing, whereas cortical full-length amyloid-?42 accumulation was comparable between Alzheimer's disease and pathological ageing. Moreover, N-terminally truncated amyloid-?42 were more likely to accumulate more in specific brain areas, especially some limbic areas, while full-length amyloid-?42 tended to accumulate more in several neocortical areas, including frontal cortices. Immunoprecipitation followed by mass spectrometry analysis showed that several N-terminally truncated amyloid-?42 species, represented by pyroglutamylated amyloid-?11-42, were enriched in these areas, consistent with ELISA results. N-terminally truncated amyloid-?42 accumulation showed significant regional association with BACE1 and neprilysin, but not PSD95 that regionally associated with full-length amyloid-?42 accumulation. Interestingly, accumulations of tau and to a greater extent apolipoprotein E (apoE, encoded by APOE) were more strongly correlated with N-terminally truncated amyloid-?42 accumulation than those of other amyloid-? species across brain areas and disease stages. Consistently, immunohistochemical staining and in vitro binding assays showed that apoE co-localized and bound more strongly with pyroglutamylated amyloid-?11-x fibrils than full-length amyloid-? fibrils. Retrospective review of clinical records showed that accumulation of N-terminally truncated amyloid-?42 in cortical areas was associated with disease onset, duration and cognitive scores. Collectively, N-terminally truncated amyloid-?42 species have spatiotemporal accumulation patterns distinct from full-length amyloid-?42, likely due to different mechanisms governing their accumulations in the brain. These truncated amyloid-? species could play critical roles in the disease by linking other clinicopathological features of Alzheimer's disease.
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Project description:Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ42) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ42 oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects vs. fibrils on synapses and protection by Aβ-phagocytic macrophages. We found that cortical neurons were more susceptible to Aβ42 oligomers than fibrils, triggering additional neuritic arborization retraction, functional alterations (hyperactivity and spike waveform), and loss of VGluT1- and PSD95-excitatory synapses. Co-culturing neurons with bone marrow-derived macrophages protected synapses against Aβ42 fibrils; moreover, immune activation with glatiramer acetate (GA) conferred further protection against oligomers. Mechanisms involved increased Aβ42 removal by macrophages, amplified by GA stimulation: fibrils were largely cleared through intracellular CD36/EEA1+-early endosomal proteolysis, while oligomers were primarily removed via extracellular/MMP-9 enzymatic degradation. In vivo studies in GA-immunized or CD115+-monocyte-grafted APPSWE/PS1ΔE9-transgenic mice followed by pre- and postsynaptic analyses of entorhinal cortex and hippocampal substructures corroborated our in vitro findings of macrophage-mediated synaptic preservation. Together, our data demonstrate that activated macrophages effectively clear Aβ42 oligomers and rescue VGluT1/PSD95 synapses, providing rationale for harnessing macrophages to treat AD.
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