The processing of the amyloid precursor protein (APP) associated with Alzheimer's disease requires the activity of membrane-bound proteases, the so-called secretases. As described in chapter 2.3.2 of my book on neurodegeneration, α-secretase cleaves the APP domain located within the plasma membrane, preventing the formation of the Aβ-peptide. In contrast, a water-soluble product (secreted APP) is formed that can even exert beneficial effects.
The proteases responsible for the formation of the Aβ-peptide are β-secretase (BACE1) and γ-secretase. Their activities lead to an accumulation of the slightly longer, not well soluble Aβ-peptides, which form oligomers and become toxic as they form β-amyloid plaques and can drive the breakdown of synaptic contacts in the brain.
Presenilins, the catalytic subunits of γ-secretase, when mutated cause a familial form of Alzheimer's disease, while ApoE4, a lipoprotein for cholesterol transport, predisposes to sporadic Alzheimer's. In a recent paper published in the prestigious journal Neuron, Thomas Südhof's team has now shown that in human neurons, chronic pharmacological or genetic suppression of γ-secretase increases the number of synapses. At the same time, synaptic transmission is reduced by a decrease in presynaptic transmitter release. The authors attribute this phenomenon to a deficiency of cholesterol in chronic inhibition of γ-secretase, since lowering cholesterol levels by classical HMG-CoA reductase inhibitors (so-called statins) also impairs synaptic function.
Previously, in embryonic mouse fibroblasts (MEFs), inhibition of γ-secretase was shown to alter lipid composition by reducing intracellular cholesterol esters and low-density lipoprotein receptor (LDLR) endocytosis. In addition, Aβ-mediated inhibition of HMG-CoA reductase reduces cholesterol synthesis. However, no studies have been performed on neurons, particularly human ones, whose cholesterol metabolism differs markedly from that of glia or peripheral cells. The present results therefore reveal for the first time a causal relationship between γ-secretase, cholesterol metabolism, and synapses in human neurons.
Thus, chronic inhibition of γ-secretase by pharmacological inhibition or deletion of presenilin (PSEN1) lowers cholesterol levels, which in turn leads to synaptic dysfunction by reducing the probability of presynaptic neurotransmitter release. However, synapse formation is probably controlled by a cholesterol-independent process, because lowering cholesterol with statins does not prevent the increase in synapse density by chronic inhibition of γ-secretase.
Because γ-secretase has numerous substrates in neurons, it is possible that multiple signaling pathways are involved (important regulators of neuronal function and synaptic organizers such as neurexins, neuroligins, cadherins, and ligands of the Notch pathway are known substrates of γ-secretase). In contrast, involvement in Alzheimer's disease-associated neuroinflammation is unlikely, because chronic inhibition of γ-secretase did not induce expression of stress or inflammatory mediators in neurons or glial cells.
However, the question remains unanswered as to why the impairment of neurotransmitter release by statins does not appear to affect cognitive performance in humans. On the one hand, statins might cause compensatory adjustments in neuronal circuitry; on the other hand, the work discussed here suggests that chronic use of statins upregulates cholesterol synthesis, which could offset any changes in the brain after initiation of these therapies.
Indeed, the potential use of statins as a treatment strategy for Alzheimer's disease has been debated for some time. Previous studies involving >20,000 patients found that individuals taking, for example, lovastatin or pravastatin for cardiovascular reasons were significantly less likely to be diagnosed with Alzheimer's disease than those receiving non-statin cardiac therapies. However, a large randomized controlled trial in the elderly found no effect on cognitive decline when statins were taken for several years.
Reference:
Essayan-Perez S, Südhof TC (2023) Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer's disease. Neuron 111:3176
Image credit: iStock/Nadzeya Haroshka