Rubbing Microglia the Right Way? At ADPD, Scientists Showcase New Strategies
Preclinical studies and early phase trials target microglial receptors CD33 and TREM2, and amyloid-stoking ASC specks.
Preclinical studies and early phase trials target microglial receptors CD33 and TREM2, and amyloid-stoking ASC specks.
Reactive astrocytes spell trouble for synapses, while microglial transform from protective to destructive as disease progresses.
The addition of SUMO2 to tau prevents its phosphorylation and aggregation, preserving synapses and memory in tauopathy mouse models.
An antibody against the inhibitory receptor LILRB4 prevented its binding to ApoE. The upshot? Microglia engulfed more Aβ fibrils and plaque load fell.
Two antibodies—one against the phosphoprotein, the other to tau’s N-terminus—restored proteostasis in the brain.
At AD/PD, scientists presented small molecules that break up fibrils and antibodies that target pathogenic forms of α-synuclein or hinder spread in iPSCs and mice.
New findings shed light on the intracellular processes that dictate tau seeding inside and between cells, and which forms are toxic to neurons.
In a small sample set, phosphorylated α-synuclein was detected in the dermis of four such disorders.
Among the many post-translational modifications of tau, sumoylation—the addition of a small ubiquitin-like modifier (SUMO) at a lysine residue—has been overlooked. Interest is growing, however, with researchers at AD/PD 2024 making a case for sumoylation influencing tau phosphorylation and pathology. In mice and cell culture, addition of SUMO1 worsened tau aggregation, while SUMO2 modification prevented it. A SUMO2 mimic rescued synapse loss in models of tauopathy.
Rather than gunning their engines, microglia can be spurred into action against amyloid plaques by letting off their brakes. An inhibitory microglial receptor, LILRB4, is upregulated around plaques in people who had had Alzheimer’s and in mouse models of amyloidosis. An antibody against LILRB4 enabled microglia to clear amyloid, reducing plaque load in the mice. How? By preventing ApoE from activating the receptor.
Scientists are in hot pursuit of disease-modifying therapies for synucleinopathies. At AD/PD 2024, a broad range of strategies were discussed, including small-molecule and antibody approaches. The former included the oligomer-buster anle138b, as well as a new candidate that breaks up fibrils by targeting a synaptic protein that co-aggregates with α-synuclein. The latter included an antibody against nitrated α-synuclein, and another that targets a receptor responsible for spread. All are in early stage trials or headed that way.
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