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.

Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer’s Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals

“…In the context of a behaving animal, we speculate that this abnormality may culminate as imbalanced neural circuits. This imbalance may eventually lead to neuronal hyperactivity and feedforward production, then subsequent accumulation of Ab before, in parallel, or in concert with previously reported postsynaptic effects (Palop and Mucke, 2016;Perdigã o et al, 2020;Sheng et al, 2012).…”

“…The SVC is at the core of the presynaptic terminal and SNARE proteins are among the most impaired proteins in our datasets. The vast majority of previous evidence points to the postsynaptic membrane as the primary site of Ab synaptic toxicity (DeBoer et al, 2014;Perdigã o et al, 2020;Serrano-Pozo et al, 2011;Sheng et al, 2012). However, the localization and processing of APP mainly occurs at presynaptic terminals, and it is not without precedence to find that APP interacts with SVs (Masliah et al, 1994a;Oddo et al, 2003).…”

Levetiracetam treatment normalizes levels of the presynaptic endocytosis machinery and restores non-amyloidogenic APP processing inAppknock-in mice

“…Several supporting lines of evidence implicate dysregulation of endocytosis and presynaptic endocytic proteins in AD thus supporting why normalization of this process reduces amyloidogenic APP processing and ultimately Aβ 42 production. Much of the previous evidence gathered on Aβ toxicity implicates the postsynaptic membrane as the primary site (DeBoer et al, 2014; Perdigão et al, 2020; Serrano-Pozo et al, 2011; Sheng et al, 2012). However, the localization and processing of APP mainly occurs at presynaptic terminals, and it has been previously shown that APP interacts with SVs (Masliah et al, 1994a; Oddo et al, 2003).…”

Early Dendritic Dystrophy in Human Brains With Primary Age-Related Tauopathy

“…In general, axonal and dendritic swelling are probably suggestive of impaired intraneuronal trafficking. Intracellular sorting and transportation of macro- and micro-molecules between the somata, dendrites, and axons are vital for the anatomical and physiological hemostasis of neurons, which are dependent on complex cellular and molecular interplays that require extensive investigations in the future (Stokin et al, 2005 ; Kimura and Yanagisawa, 2018 ; Perdigão et al, 2020 ). During intraneuronal tangle formation, pTau is disengaged from the microtubules and redistributed from the axon to the soma and dendrites (Hall and Yao, 2000 ; Spires-Jones et al, 2009 ).…”