Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by progressive memory loss. Although AD neuropathological hallmarks are extracellular amyloid plaques and intracellular tau tangles, the best correlate of disease progression is synapse loss. What causes synapse loss has been the focus of several researchers in the AD field. Synapses become dysfunctional before plaques and tangles form. Studies based on early-onset familial AD (eFAD) models have supported that synaptic transmission is depressed by β-amyloid (Aβ) triggered mechanisms. Since eFAD is rare, affecting only 1% of patients, research has shifted to the study of the most common late-onset AD (LOAD). Intracellular trafficking has emerged as one of the pathways of LOAD genes. Few studies have assessed the impact of trafficking LOAD genes on synapse dysfunction. Since endocytic traffic is essential for synaptic function, we reviewed Aβ-dependent and independent mechanisms of the earliest synaptic dysfunction in AD. We have focused on the role of intraneuronal and secreted Aβ oligomers, highlighting the dysfunction of endocytic trafficking as an Aβ-dependent mechanism of synapse dysfunction in AD. Here, we reviewed the LOAD trafficking genes APOE4, ABCA7, BIN1, CD2AP, PICALM, EPH1A, and SORL1, for which there is a synaptic link. We conclude that in eFAD and LOAD, the earliest synaptic dysfunctions are characterized by disruptions of the presynaptic vesicle exo-and endocytosis and of postsynaptic glutamate receptor endocytosis. While in eFAD synapse dysfunction seems to be triggered by Aβ, in LOAD, there might be a direct synaptic disruption by LOAD trafficking genes. To identify promising therapeutic targets and biomarkers of the earliest synaptic dysfunction in AD, it will be necessary to join efforts in further dissecting the mechanisms used by Aβ and by LOAD genes to disrupt synapses.

The increased production of the 42 aminoacids long beta-amyloid (Aβ42) peptide has been established as a causal mechanism of the familial early onset Alzheimer's disease (AD). In contrast, the causal mechanisms of the late-onset AD (LOAD), that affects most AD patients, remain to be established. Indeed, Aβ42 accumulation has been detected more than 30 years before diagnosis. Thus, the mechanisms that control Aβ accumulation in LOAD likely go awry long before pathogenesis becomes detectable. Early on, APOE4 was identified as the biggest genetic risk factor for LOAD. However, since APOE4 is not present in all LOAD patients, genome-wide association studies of thousands of LOAD patients were undertaken to identify other genetic variants that could explain the development of LOAD. PICALM, BIN1, CD2AP, SORL1, and PLD3 are now with APOE4 among the identified genes at highest risk in LOAD that have been implicated in Aβ42 production. Recent evidence indicates that the regulation of the endocytic trafficking of the amyloid precursor protein (APP) and/or its secretases to and from sorting endosomes is determinant for Aβ42 production. Thus, here, we will review the described mechanisms, whereby these genetic risk factors can contribute to the enhanced endocytic production of Aβ42. Dissecting causal LOAD mechanisms of Aβ42 accumulation, underlying the contribution of each genetic risk factor, will be required to identify therapeutic targets for novel personalized preventive strategies.

TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer’s disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.