Towards cell biology of Alzheimer’s disease

Nobel Prize laureate Prof. Thomas C. Südhof (Stanford Medicine, CA, USA) delivered an inspiring lecture, sharing a cell-biological perspective on Alzheimer's disease (AD). He focused on the role of amyloid precursor protein (APP)  and amyloid-beta (Aβ) and explained on how their combined effect this role relates to age-dependent inflammation and microglial activation.

Prof. Südhof was 1 of 3 scientists who were awarded the Nobel Prize in Physiology or Medicine in 2013 for their work on neurotransmitter release, which is the first step in synaptic transmission that accounts for the speed and precision of information transfer in the brain.

“We need to focus on a conceptual understanding of synapse loss, neuroinflammation, and neuronal cell death,” Prof. Südhof argued [1]. “This can only be achieved by a cell-biological understanding of what happens to these cells as we age.” In his talk, he largely focused on the role of APP and Aβ, and on how this relates to age-dependent inflammation and microglial activation. The combined effect of both intra-membrane and extracellular cleavage of APP leads to the release of Aβ, which subsequently aggregates into plaques. Amyloid plaques are invariably present in both familial and sporadic AD, implying that these plaques play a major role in AD, and are associated with neuronal death and inflammation. “Most AD therapies now aim to remove Aβ because it may be toxic.”

Prof. Südhof highlighted the recent results in a phase 3 trial (NCT03887455) of one of these therapies, the humanised IgG1 monoclonal antibody lecanemab, that binds with high affinity to Aβ soluble protofibrils [2]. He found the results “incredibly informative”, showing a large decrease in amyloid plaques, but only a small and “completely disproportional” beneficial effect. “Aβ plaques were nearly completely cleared, but disease progression was only slowed by 27%.” Prof. Südhof found the results hard to reconcile with the assumption that Aβ is toxic. The clinical impact may be modest, but it exists, and trials like these are invaluable in gaining a better understanding of AD, he argued. “They inform us about the disease's biology, which I think is what we should focus on.”

Prof. Südhof went on to address studies in his own lab to test the hypothesis that APP is linked to synapses which may be relevant for AD. APP mutations – like the APP^Swe mutation (KM670/671NL) – cause familial AD, and APP is a GWAS hit for AD. The results of (rigorously controlled) experiments showed that, counterintuitively, the APP^Swe mutation that causes familial AD enhances synaptic function in human neurons [3]. BACE1 inhibition was found to suppress synapses and occlude the synaptic effects of the conditional APP^Swe mutation. “In other words, it was detrimental.”

Does this imply a function for APP in synapses, Prof. Südhof then wanted to know. “Conditional APP deletion decreased the size of endosomes in human neurons. It lowered the frequency of spontaneous synaptic events as well as the synaptic strength in human neurons. So, the bottom line is that in human neurons, APP deletion produces the APP^Swe mutation's mirror-image phenotype.”

The next research question was whether this is truly mediated by Aβ or by some other cleavage product of the APP gene. Aβ secreted from HEK293 cells was found to modestly but significantly increase synaptic connectivity of cultured human neurons (similar to the APP^Swe mutation). The results suggest that APP cleavage into Aβ40 and Aβ42 under physiologically relevant conditions supports synaptic connectivity instead of impairing it. “BACE1 cleavage and gamma-secretase that cause the release of Aβ from APP, increase synaptic connectivity at physiological levels,” said Prof. Südhof. The effect size is not huge but it is robust and reproducible. If this happens chronically, Aβ clearly aggregates into plaques. This aggregation in fact serves as a kind of sink, sucking up all the Aβ, resulting in the typically lower Aβ levels in the CSF of AD patients.”

The Aβ toxicity remains unexplained. Prof. Südhof suggested the following possible explanations:

• Cross-β oligomers or aggregates could be toxic.
• Chronic decrease in free Aβ levels owing to sequestration of Aβ by Aβ aggregates could be toxic by loss of synaptic function.
• Aβ could have additional effects, like changing endosome size or function, that might be chronically altered via the formation of aggregates and sequestration of Aβ.

1. Südhof TC. Towards a cell biology of Alzheimer’s disease. EAN 2023 Annual Meeting, 1-4 July, Budapest, Hungary.
2. Van Dyck CH, et al. N Engl J Med 2023; 388:9-21.
3. Zhou B, et al. Sci Transl Med. 2022;14(667):eabn9380.

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Posted on 7 September, 202325 March, 2024