The Amyloid Precursor Protein Modulates the Position and Length of the Axon Initial Segment

Abstract

The amyloid precursor protein (APP) is linked to the genetics and pathogenesis of Alzheimer's disease (AD). It is the parent protein of the β-amyloid peptide, the main constituent of the amyloid plaques found in an AD brain. The pathways from APP to Aβ are intensively studied, yet the normal functions of APP itself have generated less interest. We report here that glutamate stimulation of neuronal activity leads to a rapid increase inAppgene expression. In mouse and human neurons, elevated APP protein changes the structure of the axon initial segment (AIS) where action potentials are initiated. The AIS is shortened in length and shifts away from the cell body. GCaMP8f Ca2+reporter confirms the predicted decrease in neuronal activity. NMDA antagonists or knockdown ofAppblock the glutamate effects. The actions of APP on the AIS are cell-autonomous; exogenous Aβ – either fibrillar or oligomeric – has no effect. In culture, APPSwe(a familial AD mutation) induces larger AIS changes than wild type APP. Ankyrin G and βIV-spectrin, scaffolding proteins of the AIS, both physically associate with APP, more so in AD brains. Finally, in humans with sporadic AD or in the R1.40 AD mouse model – both females and males – neurons have elevated levels of APP protein that invade the AIS. In vivo as in vitro, this increased APP is associated with a significant shortening of the AIS. The findings outline a new role for the APP and encourage a reconsideration of its relationship to AD.SIGNIFICANCE:While the amyloid precursor protein (APP) has long been associated with Alzheimer's disease (AD), the normal functions of the full-length Type I membrane protein have been largely unexplored. We report here that the levels of APP protein increase with neuronal activity. In vivo and in vitro, modest amounts of excess APP alter the properties of the axon initial segment (AIS). The Aβ peptide derived from APP is without effect. Consistent with the observed changes in the AIS which would be expected to decrease action potential firing, we show that APP expression depresses neuronal activity. In mouse AD models and human sporadic AD, APP physically associates with the scaffolding proteins of the AIS suggesting a relationship with AD dementia.

ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease

“…ApoER2-Dab1 signaling has been shown to regulate AβPP cleavage and Aβ synthesis in model systems [ 59 , 76 , 78 ]. AβPP is enriched in axons [ 110 , 141 ], and Aβ appears to be synthesized primarily in dystrophic axon terminals [ 91 , 137 ]. Although they are most abundant in dendritic spines, emerging evidence indicates that ApoER2 and Dab1 are also enriched in axonal growth cones [ 9 ], where they regulate arborization in a Reelin- and ApoE-dependent manner [ 21 , 81 , 102 ].…”

Contribution of Axon Initial Segment Structure and Channels to Brain Pathology

“…Moreover, AIS shortening was identified in Alzheimer’s disease mouse models or patients [ 135 , 136 , 137 ]. The absence of AIS structural plasticity was demonstrated in a frontotemporal dementia model due to a tau protein mutation identified in humans and its relation to EB1/EB3 proteins and microtubules in the AIS [ 138 ].…”

Homeostatic plasticity of axonal excitable sites in Alzheimer's disease

“…This effect was mediated by Aβ inhibition of histone deacetylase 6 (HDAC6), as applying tubacin (a HDAC6 inhibitor) increased EB3 dynamics at the AIS and lengthened the AIS, similar to Aβ application. A recent study suggests that APP overexpression induced by glutamate excitotoxicity, or by overexpression via plasmid transfection carrying the APP Swe mutation or using transgenic (R1.40 model) primary neurons, drives the modifications in AIS structure (Ma et al, 2023 ). Elevated concentration of APP, which contacts the AIS scaffolding proteins ankyrin G and βIV-spectrin, promoted an AIS shift away from the soma and a shortening of the AIS.…”

“…Although AD is a complex disease that alter many cellular mechanisms with divergent effects on neural circuits, initial Aβ rise can be broadly associated with network hyperactivity, while the later accumulation of tau can be associated with network hypoactivity (Harris et al, 2020 ). The initial hyperactivity may explain the finding of short AISs when Aβ plaque load is severe (Marin et al, 2016 ), when soluble Aβ accumulates (Martinsson et al, 2022 ) and when APP is overexpressed (Martinsson et al, 2022 ; Ma et al, 2023 ). An AIS shortening is expected to reduce neuronal excitability to compensate for prolonged hyperactivity in healthy neurons (although it is not always the case; see Adachi et al, 2015 ).…”

“…An AIS shortening is expected to reduce neuronal excitability to compensate for prolonged hyperactivity in healthy neurons (although it is not always the case; see Adachi et al, 2015 ). The AIS distal shift found in association with APP overexpression is also expected to lower the neuronal excitability (Ma et al, 2023 ). In addition, larger GABAergic synapses at the AIS in the APP NL − F model reinforce the suggestion that the AIS reshapes to counter network hyperexcitability (Sos et al, 2020 ).…”