Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer's Disease

Abstract

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.

Keywords: APOE4; BIN1; CD2AP; PICALM; endocytosis; late-onset Alzheimer’s disease; synapses; β-amyloid.

Figure 1

Gene ontology (GO) analysis of LOAD risk factors reveals the enrichment of genes in the trafficking pathway. Nearly half of the 37 LOAD putative risk factors identified by genome-wide association studies (GWAS) meta-analysis (Lambert et al., ; Jansen et al., ; Kunkle et al., 2019), have been functionally grouped by GO analysis in three main pathways: trafficking (orange), immune response (blue), and lipid metabolism (green). GO analysis was performed using the Cytoscape StringApp (Doncheva et al., 2019).

Figure 2

Scheme illustrating how Aβ impacts synaptic trafficking. Scheme of a dysfunctional early-onset familial AD (eFAD) synapse. At the presynaptic terminal: 1. Synaptic vesicle release inhibition, extracellular Aβ endocytosed, alone or via ApoE-LRP endocytosis can accumulate at endosomes. Intracellular Aβ, produced from APP endocytosis, accumulates at endosomes. Endosomal Aβ can disrupt the endosomal membrane and reach the cytosol, where it can potentially bind to SNARE subunit syntaxin-1a, or indirectly inhibit synaptophysin or PIP2, thus inhibiting synaptic vesicles (SV) fusion and neurotransmitter release. 2. SV endocytosis inhibition, extracellular Aβ increases calcium influx, triggers calcium-dependent calpain to degrade dynamin1, reducing endocytosis. 3. SV recycling inhibition by intracellular Aβ. 4. Transport to synapses inhibition by intracellular Aβ oligomerization. At the postsynaptic terminal: 5. Increased endocytosis of AMPA and NMDA receptors, by intracellular and extracellular Aβ. 6. Loss of PSD-95 by intracellular Aβ. 7. Impaired endosomal sorting of TrkB receptor, by endosomal Aβ.

Figure 3

Scheme of a dysfunctional LOAD synapse illustrating how LOAD trafficking genes impact synaptic trafficking. At the presynaptic terminal, 1. Sorl1 and Cindr (CD2AP homolog) interact with synapsin, via 14–3–3, and their loss of function leads to aberrant synapsin accumulation. 2. CALM mediates VAMP2 endocytosis and SNARE complex recycling. 3. Bin1 interacts with dynamin and SV2 and could play a role in SV endocytosis. 4. ApoE4 and ABCA7 alter the transport of cholesterol and other lipids into neurons, leading to cholesterol retention in recycling endosomes and depletion from the synaptic membranes. At the postsynaptic terminal, 5. Sorl1 attenuates EphA4 activation by ephrinA1, causing spine retraction. 6. Bin1 regulates GluA1 availability at synapses via recycling. 7. CALM regulates GluA2 availability at synapses via endocytosis. 8. ApoE4 regulates AMPA receptor availability at synapses via calcium influx, calcineurin activation, that dephosphorylates AMPA receptors triggering their endocytosis.