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 Ca2+ 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.
Triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in regulating microglial function in Alzheimer’s disease (AD) and other neurodegenerative disorders. Genetic studies have identified rare coding variants in TREM2 as significant risk factors for late-onset AD (LOAD), highlighting the importance of disrupted microglial signaling in disease pathogenesis. Biochemically, TREM2 acts as a receptor for lipid- and damage-associated molecular patterns, recognizing anionic phospholipids, myelin-derived lipids, apolipoproteins, and aggregated amyloid-β (Aβ). It engages with adaptors like DAP12 and DAP10, activating key signaling pathways, including SYK, PI3K-AKT-mTOR, and PLCγ2, leading to microglial transcriptional and metabolic reprogramming. These processes are essential for the transition of microglia to disease-associated microglia (DAM), influencing amyloid plaque compaction and tau pathology propagation. This review aims to synthesize the latest insights into TREM2 biology, focusing on the role of TREM2 in microglial state transitions, lipid metabolism, and myelin turnover. It also examines the pathophysiological relevance of soluble TREM2 (sTREM2) and AD-associated TREM2 variants. Furthermore, the review explores the therapeutic potential of targeting TREM2, including strategies based on agonistic antibodies and modulation of receptor shedding. Beyond prior descriptive summaries, we organize these findings within a stage-resolved immunometabolic framework that links disease timing, lipid-stress context, and microglial state transitions. This framework is intended to explain why similar TREM2-directed interventions may yield different outcomes across disease stages and pathology compositions. We further highlight stage-specific translational logic, including biomarker-informed (e.g., sTREM2-guided) stratification and monitoring, to support testable and clinically actionable trial designs.
