|Alzheimer risk-increasing TREM2 variant causes aberrant cortical synapse density and promotes network hyperexcitability in mouse models.
|Year of Publication
|Das M, Mao W, Voskobiynyk Y, Necula D, Lew I, Petersen C, Zahn A, Yu G-Q, Yu X, Smith N, Sayed FA, Gan L, Paz JT, Mucke L
|2023 Oct 01
|Alleles, Alzheimer Disease, Amyloid beta-Peptides, Animals, Disease Models, Animal, Humans, Membrane Glycoproteins, Mice, Plaque, Amyloid, Receptors, Immunologic, Seizures, Synapses
The R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2) increases the risk of Alzheimer's disease (AD). To investigate potential mechanisms, we analyzed knockin mice expressing human TREM2-R47H from one mutant mouse Trem2 allele. TREM2-R47H mice showed increased seizure activity in response to an acute excitotoxin challenge, compared to wildtype controls or knockin mice expressing the common variant of human TREM2. TREM2-R47H also increased spontaneous thalamocortical epileptiform activity in App knockin mice expressing amyloid precursor proteins bearing autosomal dominant AD mutations and a humanized amyloid-β sequence. In mice with or without such App modifications, TREM2-R47H increased the density of putative synapses in cortical regions without amyloid plaques. TREM2-R47H did not affect synaptic density in hippocampal regions with or without plaques. We conclude that TREM2-R47H increases AD-related network hyperexcitability and that it may do so, at least in part, by causing an imbalance in synaptic densities across brain regions.
|PubMed Central ID
|F32 NS127998 / NS / NINDS NIH HHS / United States
RF1 AG063519 / AG / NIA NIH HHS / United States