Synaptic roles for neurofilament proteins have rarely been considered. Here, we establish all four neurofilament subunits as integral resident proteins of synapses. Compared to the population in axons, neurofilament subunits isolated from synapses have distinctive stoichiometry and phosphorylation state, and respond differently to perturbations in vivo. Completely eliminating neurofilament proteins from brain by genetically deleting three subunits (α-internexin, NFH and NFL) markedly depresses hippocampal LTP induction without detectably altering synapse morphology. Deletion of NFM in mice, but not the deletion of any other neurofilament subunit, amplifies dopamine D1-receptor-mediated motor responses to cocaine while redistributing postsynaptic D1-receptors from endosomes to plasma membrane, consistent with a specific modulatory role of NFM in D1-receptor recycling. These results identify a distinct pool of synaptic neurofilament subunits and establish their key role in neurotransmission in vivo, suggesting potential novel influences of neurofilament proteins in psychiatric as well as neurological states.
The cerebral deposition of amyloid -peptide, a central event in Alzheimer's disease (AD) pathogenesis, begins several years before the onset of clinical symptoms. Noninvasive detection of AD pathology at this initial stage would facilitate intervention and enhance treatment success. In this study, high-field MRI was used to detect changes in regional brain MR relaxation times in three types of mice: 1) transgenic mice (PS/APP) carrying both mutant genes for amyloid precursor protein (APP) and presenilin (PS), which have high levels and clear accumulation of -amyloid in several brain regions, starting from 10 weeks of age; 2) transgenic mice (PS) carrying only a mutant gene for presenilin (PS), which show subtly elevated levels of A-peptide without -amyloid deposition; and 3) nontransgenic Cerebral deposits of the amyloid -peptide and alterations of neurophysiology develop some years before Alzheimer's disease can be diagnosed clinically (1-3). By this stage, brain pathology is extensive and includes irreversible loss of neurons in brain regions essential for normal cognition (3). Because AD therapy is likely to be most successful when intervention occurs before neurons are irreversibly damaged or lost, noninvasive methods to detect early yet subtle changes in the brain would have considerable clinical value. Currently, there are no sensitive and specific biological markers for the preclinical stages of AD.Recent MRI studies of humans with mild cognitive impairment have shown that brain volume losses associated with neurodegeneration in the hippocampus have value in predicting increased risk for developing AD (4,5). Moreover, advances in high field strength MRI technology now raise the possibility that more subtle alterations of morphology or physiology preceding neurodegeneration might be detectable, including, in the case of AD, early effects of -amyloid deposition. Since intrinsic MR parameters, such as transverse (T 2 ) and longitudinal (T 1 ) relaxation times are sensitive to changes in the biophysical environment of water, we hypothesized that the presence of increased deposition of -amyloid in the brain would have an effect on these parameters.To investigate the possibility of early detection of the pathophysiology associated with AD, we studied PS/APP and PS transgenic mice together with nontransgenic (NTg) controls with MRI at 7 T. PS transgenic mice carry only a mutant gene for presenilin-1 (PS), which show subtly elevated levels of A-peptide without -amyloid deposition in the brain (6). PS/APP transgenic mice express the human genes for amyloid precursor protein (APP) and presenilin-1 (PS) (7), which harbor mutations, APP K670N,M671L and PS M146V , known to cause familial AD (FAD) in humans. In these mice, -amyloid begins to deposit at 10 -12 weeks of age and progressively accumulates as plaque-like lesions throughout their life span, reaching levels exceeding those in AD brain. Several other features of the human disease are also seen, including dystrophy of some neurites and mild local inf...
In this study, we used MRI to analyze quantitative parametric maps of transverse (T 2 ) relaxation times in a longitudinal study of transgenic mice expressing mutant forms of amyloid precursor protein (APP), presenilin (PS1), or both (PS/APP), modeling aspects of Alzheimer's disease (AD). The main goal was to characterize the effects of progressive b-amyloid accumulation and deposition on the biophysical environment of water and to investigate if these measurements would provide early indirect evidence of AD pathological changes in the brains of these mice. Our results demonstrate that at an early age before b-amyloid deposition, only PS/APP mice show a reduced T 2 in the hippocampus and cortex compared with wild-type non-transgenic (NTg) controls, whereas a statistically significant within-group aging-associated decrease in T 2 values is seen in the cortex and hippocampus of all three transgenic genotypes (APP, PS/APP, and PS) but not in the NTg controls. In addition, for animals older than 12 months, we confirmed our previous report that only the two genotypes that form amyloid plaques (APP and PS/APP) have significantly reduced T 2 values compared with NTg controls. Thus, T 2 changes in these AD models can precede amyloid deposition or even occur in AD models that do not deposit b-amyloid (PS mice), but are intensified in the presence of amyloid deposition.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.