A novel nodal β-amyloid hypothesis for Alzheimer’s disease: validating Nav1.6 as a potential therapeutic target

Amyloid precursor protein (APP) plays key roles in apoptosis, synaptic plasticity, neurogenesis, learning, and memory, but its exact physiological distribution and function along myelinated axons have not been established. We recently showed that APP: (i) specifically clusters at the initial segments (ISs) and nodes of Ranvier (NORs) of CNS axons1 and (ii) modulates Nav1.6 sodium channels through a Go-coupled JNK pathway dependent on APP phosphorylation at Thr6682. The perforant pathway (formed from myelinated axons) originates from the entorhinal cortex and is severely affected in Alzheimer’s disease (AD), particularly during its earlier stages3. Based on these observations, we hypothesise that APP at NORs modulates sodium channel function to affect neuronal excitability and correlates with β-amyloid (Aβ) deposition along the perforant pathway at AD onset (Fig. 1). This proposal tests this hypothesis using a combined experimental pathology and behavioural testing approach and, furthermore, addresses whether the axonal sodium channel Nav1.6 is a potential therapeutic target in AD. Our systematic approach will demonstrate that APP is an important component of perforant pathway NORs and not only modulates nodal formation but also participates in AD pathology. This study aims to reveal new pathogenetic mechanisms in AD and provide a fundamental platform for further preclinical development and targeted drug screening for AD treatment. We will accomplish these goals via two specific aims: Aim 1: To define the physiological and pathological distribution of APP along perforant pathway axons. APP is expressed in axons and is a marker of axonal degeneration4, but its physiological distribution along perforant pathway axons is unknown. The perforant pathway is the most severely affected area in AD, particularly during its early stages3, and electrical activity within the pathway modulates interstitial fluid Aβ levels and can be blocked by tetrodotoxin (TTX), a specific sodium channel blocker5,6. Thus, we will investigate whether APP distribution along myelinated axons correlates with Aβ deposition along the perforant pathway. Aim 2: To determine whether sodium channel Nav1.6 is a potential therapeutic target in AD. To test the hypothesis that Nav1.6 is a potential therapeutic target in AD, APP/presenilin 1 (PS1) mice (a well-established AD model) will be subjected to sodium channel blockade (TTX) and AD pathology systematically analysed using tissue-based and behavioural assays. This ultimate aim is to expand this initial candidate drug approach to screening subtype-selective Nav1.6 inhibitors to further advance the drug development pipeline in AD.