Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer's disease-relevant brain circuits.

Rare mutations in the gene encoding presenilin2 (PSEN2) are known to cause familial Alzheimer's disease (FAD). Here, we explored how altered PSEN2 expression impacts on the amyloidosis, endolysosomal abnormalities, and synaptic dysfunction observed in female APP knock-in mice. We demonstrate that PSEN2 knockout (KO) as well as the FAD-associated N141IKI mutant accelerate AD-related pathologies in female mice.

Inhibition of an Alzheimer's disease-associated form of necroptosis rescues neuronal death in mouse models.

Necroptosis is a regulated form of cell death that has been observed in Alzheimer's disease (AD) along with the classical pathological hallmark lesions of amyloid plaques and Tau neurofibrillary tangles. To understand the neurodegenerative process in AD, we studied the role of necroptosis in mouse models and primary mouse neurons. Using immunohistochemistry, we demonstrated activated necroptosis-related proteins in transgenic mice developing Tau pathology and in primary neurons from amyloid precursor protein (APP)-Tau double transgenic mice treated with phosphorylated Tau seeds derived from a patient with AD but not in APP transgenic mice that only exhibited β-amyloid deposits.

Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model.

Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental conditions. We overcame these limitations by conducting the first longitudinal controlled experiment evaluating genotype and GTE-EGCG prenatal chronic treatment effects before and after treatment discontinuation.

An immunological puzzle: The adaptive immune system fuels Alzheimer's disease pathology.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a concerning rise in prevalence. It is projected that the number of affected individuals will reach a staggering 150 million by 2050. While recent advancements in monoclonal antibodies targeting Aβ have shown some clinical effects, there is an urgent need for improved therapies to effectively address the impeding surge of AD patients worldwide.

Neurobeachin haploinsufficient mice display sex-independent alterations in cued and contextual fear conditioning.

Neurobeachin ( NBEA ) is a cytoplasmic protein that regulates receptor trafficking, neurotransmitter and hormone secretion, as well as synaptic connectivity. Recently, hippocampus-dependent contextual extinction, the gradual decrease of a conditioned fear response to a context, was suggested to be specifically impaired in male mice with Nbea deficiency ( Nbea+/- ). The current study examines the role of sex in this effect and whether Nbea also influences cued fear conditioning.