Presenilin deficiency beyond amyloid: Lessons from presenilin 1/2 conditional double-knockout mice on synaptic failure, calcium dyshomeostasis, and inflammation-driven Alzheimer’s disease

ABSTRACT Presenilins are best known as the catalytic core of γ-secretase, where familial Alzheimer’s disease (FAD) mutations shift amyloid-β (Aβ) trimming toward aggregation-prone species. Yet conditional and cell-type-specific genetic analyses in mice now place presenilin (PS) biology far beyond amyloidogenesis. In PS1/PS2 conditional double-knockout (PS cDKO) models, where presenilins are inactivated postnatally in forebrain excitatory neurons, the earliest phenotype is a synaptopathy: presynaptic release probability and short-term plasticity collapse, N-methyl-D-aspartate receptor (NMDAR) function wanes, and cAMP response element-binding protein (CREB)/CREB-binding protein (CBP)-dependent transcriptional programs falter. Compensatory glial responses rapidly consolidate into a neuroinflammatory state, with inflammasome activation and cytokine surges that further erode synaptic signaling and promote tau hyperphosphorylation. Progressive cortical and callosal atrophy and ventriculomegaly follow, culminating in neuron loss, even as cortical Aβ is reduced, severing the mechanistic necessity of plaques for degeneration. Across interventions, anti-inflammatory, cholinergic, and metabolic manipulations rescue cognition and plasticity in PS cDKO mice without engaging amyloid, underscoring a disease axis that is Aβ-independent yet clinically salient. Here we synthesize lessons from PS cDKO studies, integrate them with contemporary presenilins/γ-secretase biology, and outline a translational agenda focused on presynaptic Ca 2+ microdomains, RyR-coupled release, activity-dependent gene programs, and innate immune checkpoints. We conclude that PS integrate vesicular release machinery with trophic and inflammatory homeostasis; their loss initiates a multi-scale failure cascade that redefines early AD-related neurodegeneration beyond Aβ.