Abstract
Reductions in hippocampal neurite complexity and synaptic plasticity are believed to contribute to the progressive impairment in episodic memory and the mild cognitive decline that occur particularly in the early stages of Alzheimer's disease (AD). Despite the functional and therapeutic importance for patients with AD, intervention to rescue or normalize dendritic elaboration and synaptic plasticity is scarcely provided. Here we show that overexpression of neuritin, an activity-dependent protein, promoted neurite outgrowth and maturation of synapses in parallel with enhanced basal synaptic transmission in cultured hippocampal neurons. Importantly, exogenous application of recombinant neuritin fully restored dendritic complexity as well as spine density in hippocampal neurons prepared from Tg2576 mice, whereas it did not affect neurite branching of neurons from their wild-type littermates. We also showed that soluble recombinant neuritin, when chronically infused into the brains of Tg2576 mice, normalized synaptic plasticity in acute hippocampal slices, leading to intact long-term potentiation. By revealing the protective actions of soluble neuritin against AD-related neural defects, we provide a potential therapeutic approach for patients with AD.
Highlights
Neuritin, known as the candidate plasticity gene 15, was originally identified in a screening study for activityregulated genes and was subsequently found to be one of the signaling molecules downstream to brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase receptor type B.16,17 Ensuing studies indicated that neuritin could be induced by experimental seizure or by normal life experiences, such as sensory stimulation and exercise.[17,18,19,20,21,22] Located in the 6p24p25 interval on chromosome 6,23 the neuritin gene encodes a small, highly conserved protein containing a secretory signal sequence at the N-terminus and a consensus sequence for glycosylphosphatidylinositol (GPI) at the C-terminus.[16]
As the outgrowth of neurites starts early in postnatal development,[29,33] hippocampal neurons in culture were transfected at 3 days in vitro (DIV) and analyzed 3 days later
Those transfected neurons were identified with the expression of eGFP or neuritin-Flag that was labeled with Alexa Fluor 488, because the intensity of the eGFP signal itself from pIRES-eGFP-neuritin-Flag tended to be weak
Summary
Known as the candidate plasticity gene 15, was originally identified in a screening study for activityregulated genes and was subsequently found to be one of the signaling molecules downstream to BDNF and its receptor tropomyosin-related kinase receptor type B.16,17 Ensuing studies indicated that neuritin could be induced by experimental seizure or by normal life experiences, such as sensory stimulation and exercise.[17,18,19,20,21,22] Located in the 6p24p25 interval on chromosome 6,23 the neuritin gene encodes a small, highly conserved protein containing a secretory signal sequence at the N-terminus and a consensus sequence for glycosylphosphatidylinositol (GPI) at the C-terminus.[16]. Known as the candidate plasticity gene 15, was originally identified in a screening study for activityregulated genes and was subsequently found to be one of the signaling molecules downstream to BDNF and its receptor tropomyosin-related kinase receptor type B.16,17. We determined that neuritin expression increased neurite complexity and promoted the maturation of individual spines in cultured hippocampal neurons. Consistent with these findings, basal synaptic transmission was enhanced by
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