Interdependence of neural network dysfunction and microglial alterations in Alzheimer’s disease-related models

Abstract

Summary Nonconvulsive epileptiform activity and microglial alterations have been detected in people with Alzheimer’s disease (AD) and related mouse models. However, the relationship between these abnormalities remains to be elucidated. We suppressed epileptiform activity by treatment with the antiepileptic drug levetiracetam or by genetic ablation of tau and found that these interventions reversed or prevented aberrant microglial gene expression in brain tissues of aged human amyloid precursor protein transgenic mice, which simulate several key aspects of AD. The most robustly modulated genes included multiple factors previously implicated in AD pathogenesis, including TREM2, the hypofunction of which increases disease risk. Genetic reduction of TREM2 exacerbated epileptiform activity after mice were injected with kainate. We conclude that AD-related epileptiform activity markedly changes the molecular profile of microglia, inducing both maladaptive and adaptive alterations in their activities. Increased expression of TREM2 seems to support microglial activities that counteract this type of network dysfunction.

Pharmacokinetic, pharmacodynamic, and transcriptomic analysis of chronic levetiracetam treatment in 5XFAD mice: A MODEL‐AD preclinical testing core study

“…These data are consistent with recent work that showed that treatment with LEV in aged hAPP mice prevented aberrant microglia gene expression. 36 The authors suggest that epileptiform activity observed in this model influences microglia directly, and that the reduction of the microglial gene TREM2 exacerbates this activity. This is consistent with the known regulation of phagocytosis via TREM2‐activation of PLCG2, 20 , 21 which would result in impaired amyloid clearance in this model.…”

“…Based on the proposed mechanism of action of LEV as a neuromodulator of synaptic transmission, 1,7 these results were not surprising, and suggest that earlier treatment and longer duration with LEV may be required to accomplish this outcome, and are consistent with a number of preclinical studies that have used LEV in amyloid models. 14,16,36 Functional testing revealed dose-dependent increases in hyperactivity (Figure 4), which may be indicative of potential side effect profile of LEV. However, given the therapeutic index for the dose range based on PK/PD and in consideration of the allometric scaling data, the dose range for side effects relative to the efficacious dose range may not be a major concern.…”

Higher susceptibility to 6 Hz corneal kindling and lower responsiveness to antiseizure drugs in mouse models of Alzheimer's disease

“…Different groups looked at the effect of tau reduction on seizure susceptibility, with or without the presence of amyloid alterations and most found that tau reduction led to less‐severe seizures. 12 , 43 , 44 …”

“…Different groups looked at the effect of tau reduction on seizure susceptibility, with or without the presence of amyloid alterations and most found that tau reduction led to less-severe seizures. 12,43,44 One report of a study of seizures in an AD model with both amyloid and tau mutations showed that 3xTg mice were more susceptible to audiogenic seizures at the age of 3 weeks. 13 Biomarker analysis was limited to IHC with the 6E10 antibody, which demonstrated the presence of Aβ or APP in HC neurons.…”

APOE Expression and Secretion are Modulated by Mitochondrial Dysfunction

“…This neuroinflammatory panel reports the activity of 23 neuroinflammation pathways and processes across five brain cell types and 14 cell types of the peripheral immune system. We chose this approach since it is validated in Alzheimer’s models, highly sensitive, and measures mRNAs without cDNA amplification (Das et al, 2021; Ramesha et al, 2021). We performed NanoString quantification in wild type, SLC25A1Δ , and SLC25A4Δ HAP1 cells, as well as in iPSC-derived astrocytes treated for 48 hours with sublethal doses of antimycin (Fig.…”