International Business Department           Liu Bojia           March 14, 2023

  More than a century ago, German psychiatrist Alois Alzheimer saw and treated a patient who suffered from a peculiar condition that was accompanied by short-term memory loss and cognitive dysfunction. As her condition worsened, the patient eventually passed away from this strange disease.

  After testing samples of her brain, Dr Alzheimer's discovered two distinctive features - neuroinflammatory plaques and neurotangles - and the disease with similar symptoms and pathological features was subsequently named Alzheimer's disease (AD). In subsequent years of research, beta amyloid (Aβ) plaques and neural tangles caused by Tau proteins became the focus of the AD research field. And the first AD treatment drug fully approved by the FDA in nearly 20 years works by reducing amyloid deposits in the brain.

  However, Aβ plaques and neurotangles were not all that Dr Alzheimer found in the first place, as he had also pointed out in his sample descriptions the presence of lipid vesicles inside glial cells in the brains of patients. However, this pathological feature of glial cells and lipids (glial-lipid) has not received much attention.

  In a weighty paper published in Nature on 14 March from Professor Tony Wyss-Coray's team at Stanford University, the team discovered a microglia state defined by the lipid droplet-associated enzyme ACSL1. According to the paper, those patients with the genotype APOE4/4 have a higher number of microglia expressing ACSL1 and there is a link between the genetic risk of AD development and the accumulation of lipid droplets in microglia, a finding that may lead to novel therapeutic targets and strategies for AD therapies.

  The APOE gene is responsible for encoding apolipoprotein E, which is involved in the conversion and metabolism of lipoproteins in cells. It is also an important genetic predictor of the risk of developing AD, with people carrying two copies of APOE4 having a significantly higher risk of developing AD compared to those carrying APOE3.

  For the new study, the authors collected cortical tissue samples from AD patients with the APOE4/4 genotype and analysed them for single nucleus RNA sequencing, while controls were samples from AD patients with APOE3/3. The study generated about 100,000 single-nucleus transcriptomes in the major cell types of the brain, and they focused on differences in microglia.

  The microglia of APOE4/4 individuals, compared to controls, differed most in the gene encoding the lipid-processing enzyme ACSL1, which happens to be key to lipid droplet biogenesis. And similarly to those lipid-filled cells that mostly clustered around Aβ plaques based on analysis of cellular staining of the samples, those microglia expressing ACSL1 also tended to cluster near Aβ plaques, suggesting that the two may be the same type of cell.

  In addition, the authors introduced fibrillar Aβ into a microglia model of induced pluripotent stem cell generation, which directly induced cellular ACSL1 expression, triglyceride synthesis, and accumulation of lipid droplets, and the above changes were significantly higher in cells of the APOE4/4 genotype.

  The authors noted that the high expression of ACSL1 can already be used to define a distinct state of microglia, which they termed LDAM, representing microglia that are associated with lipid droplets and associated with disease. LDAM is more prevalent in the brains of individuals with AD compared to healthy individuals , and is particularlyenriched in individuals with theAPOE4/4genotype.

  Observations showed that neurons in AD patients do not upregulate ACSL1, so they speculated that the excess lipids found in neurons may also originate from microglia. Although a century removed from Dr Alzheimer's discovery, the new study finally confirms that lipid accumulation is indeed driving the onset and progression of AD, and that the process is mediated by LDAM, a finding that may lead to entirely new targets and directions for the development of therapeutic strategies for AD in the future.