Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


This content will become publicly available on June 1, 2027

Title: D-methionine improves spatial navigation and attenuates oxidative stress and amyloid pathology in a sex-specific manner
BackgroundOxidative stress and maladaptive neuroimmune activation contribute to cognitive decline in Alzheimer's disease (AD) and represent therapeutic targets beyond amyloid-centered approaches. ObjectiveTo determine whether oral D-methionine (D-Met), a redox-active amino acid, reduces amyloid pathology and lipid peroxidation and confers disease-modifying benefits in AD models. MethodsMale and female APP/PS1 and APPNL−Fmice with advanced AD pathology received oral D-Met or vehicle. Behavioral assessments included locomotor activity and hippocampal-dependent spatial learning and memory. Amyloid burden, lipid peroxidation, peripheral metabolic, and inflammatory markers, and hippocampal microglial phenotypes were evaluated. ResultsD-Met did not alter locomotor or exploratory behavior but improved spatial memory recall in both sexes of APP/PS1 mice and in female APPNL−Fmice. APPNL−Fmales exhibited improved Morris water maze learning. Amyloid pathology was region-specifically reduced, including decreased hippocampal plaque size in male APPNL−Fmice, reduced cortical plaque size in female APP/PS1 mice, and lower soluble amyloid-β (Aβ)42in male APP/PS1 mice. Lipid peroxidation was reduced only in female APPNL−Fmice. D-Met induced pronounced sex-dependent peripheral effects, increasing adiposity and pro-inflammatory adipose signaling in males, while reducing perigonadal white adipose tissue IL-6 expression in female APPNL−Fmice. In the hippocampus, D-Met decreased microglial activation, with female APPNL−Fmice showing reduced Iba1 and disease-associated microglial markers and increased Axl expression. ConclusionsShort-term D-Met acts as a metabolic and redox modulator with amyloid-lowering effects mediated by improved microglial function. Therapeutic efficacy is strongly sex- and model-dependent, with the greatest benefit observed in female APPNL−Fmice.  more » « less
Award ID(s):
2301723
PAR ID:
10706922
Author(s) / Creator(s):
; ; ; ; ; ; ; ;
Publisher / Repository:
Journal of Alzheimer’s Disease
Date Published:
Journal Name:
Journal of Alzheimer’s Disease
Volume:
111
Issue:
4
ISSN:
1387-2877
Page Range / eLocation ID:
1807 to 1819
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; ; ; ; ; ; ; ; et al (, Frontiers in Aging Neuroscience)
    Introduction Alzheimer's disease (AD) is a progressive neurodegenerative disease. The early processes of AD, however, are not fully understood and likely begin years before symptoms manifest. Importantly, disruption of the default mode network, including the hippocampus, has been implicated in AD. Methods To examine the role of functional network connectivity changes in the early stages of AD, we performed resting-state functional magnetic resonance imaging (rs-fMRI) using a mouse model harboring three familial AD mutations ( App NL-G-F/NL-G-F knock-in, APPKI) in female mice in early, middle, and late age groups. The interhemispheric and intrahemispheric functional connectivity (FC) of the hippocampus was modeled across age. Results We observed higher interhemispheric functional connectivity (FC) in the hippocampus across age. This was reduced, however, in APPKI mice in later age. Further, we observed loss of hemispheric asymmetry in FC in APPKI mice. Discussion Together, this suggests that there are early changes in hippocampal FC prior to heavy onset of amyloid β plaques, and which may be clinically relevant as an early biomarker of AD. 
    more » « less
  2. ; ; ; ; ; ; ; ; ; ; et al (, eneuro)
    Alzheimer’s disease (AD) is the most common form of dementia and results in neurodegeneration and cognitive impairment. White matter (WM) is affected in AD and has implications for neural circuitry and cognitive function. The trajectory of these changes across age, however, is still not well understood, especially at earlier stages in life. To address this, we used theAppNL-G-F/NL-G-Fknock-in (APPKI) mouse model that harbors a single copy knock-in of the human amyloid precursor protein (APP) gene with three familial AD mutations. We performedin vivodiffusion tensor imaging (DTI) to study how the structural properties of the brain change across age in the context of AD. In late age APPKI mice, we observed reduced fractional anisotropy (FA), a proxy of WM integrity, in multiple brain regions, including the hippocampus, anterior commissure (AC), neocortex, and hypothalamus. At the cellular level, we observed greater numbers of oligodendrocytes in middle age (prior to observations in DTI) in both the AC, a major interhemispheric WM tract, and the hippocampus, which is involved in memory and heavily affected in AD, prior to observations in DTI. Proteomics analysis of the hippocampus also revealed altered expression of oligodendrocyte-related proteins with age and in APPKI mice. Together, these results help to improve our understanding of the development of AD pathology with age, and imply that middle age may be an important temporal window for potential therapeutic intervention. 
    more » « less
  3. ; ; ; ; ; ; ; ; ; ; et al (, Brain)
    Abstract Alzheimer’s Disease (AD) is an age-dependent neurodegenerative disorder and represents the most common type of dementia, increasing in incidence at an alarming rate in the aging population. The hallmarks of the disease are amyloid plaque accumulation, microglia and astrocyte activation, and loss of presynaptic structure leading to cognitive decline. Recently, oligodendrocyte (OL) and myelin abnormalities have emerged as important contributors to the pathogenesis of AD. In normal brain homeostatic conditions, OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. How strengthening OL function may support neuronal health in AD neurodegeneration remains to be fully characterized and represents a gap in knowledge and a missed therapeutic opportunity. This study sought to examine how myelin and OL may improve neuronal deficits associated with AD. We have generated a novel mouse model (AD/cKO) by crossing the AppNL-G-F mouse, an established AD model, which carries three human AD mutations in the mouse App gene, with the FusOLcKO whose OL depleted of Fus (Fused in Sarcoma) produce thicker myelin associated with greater cholesterol biosynthesis. We evaluated spatial memory function with standardized cognitive testing. We evaluated microglia density and state, astrocytic activation and toxic phenotype, myelin density, cholesterol content, amyloid plaque burden, presynaptic structures, and neuronal hypoxic and oxidative damage in the hippocampus and cortex. We characterized the transcriptome of AD/cKO hippocampal OL compared to AD by using single-cell transcriptomic studies. Spatial working memory was fully preserved in the aged AD/cKO mouse relative to the AD mouse. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the amyloid plaque niches, and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, amyloid plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Fus dependent myelin increase was present in both hippocampus and cortex. Single-cell transcriptomics of AD/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in mediating protection of neurons and affecting microglia state in AD pathology. This work provides new insight into how oligodendrocytes may protect neurons in AD, communicate with other glial cellular players, and point to potential targets for disease intervention aimed at slowing AD progression. 
    more » « less
  4. ; ; ; ; ; ; ; ; ; (, Scientific Reports)
    We developed a high-throughput imaging workflow to spatially map Alzheimer’s disease (AD) pathology in postmortem hippocampal and medial temporal lobe sections from 65 University of Southern California Alzheimer's Disease Research Center (USC ADRC) cases classified by low, intermediate and high levels of AD neuropathologic change (ADNC). Sections were stained for microglia (Iba1), amyloid-β (4G8), and neurofibrillary tangles (NFTs; Gallyas), and analyzed using pixel-based machine learning (Ilastik). Amyloid pathology was classified as dense, diffuse, or intracellular amyloid precursor protein (APP)-positive; microglia were categorized into ramified, rod-like, and amoeboid morphologies. Diffuse amyloid plaques increased most significantly across disease, particularly in the subiculum and dentate gyrus molecular layer, while dense plaques and intracellular APP were concentrated in entorhinal and perirhinal cortices. NFT burden was elevated in males, especially in parahippocampal cortical areas. Microglial morphology shifted with AD progression, showing reduced ramified and increased amoeboid profiles in high ADNC cases. Rod microglia in CA regions were correlated with amyloid in high ADNC and tau in low ADNC cases. Memory impairment correlated more strongly with amyloid pathology in apolipoprotein E (ApoE) ε4 non-carriers, with females showing greater amyloid burden and males more NFT-related decline. These findings reveal region- and sex-specific patterns of pathology and neuroinflammation, offering new insights into mechanisms driving cognitive decline and informing future diagnostic and therapeutic strategies. 
    more » « less
  5. ; ; ; ; ; ; ; ; ; ; et al (, Alzheimer's & Dementia)
    Abstract INTRODUCTIONThis study aimed to investigate whether sleep quality predicts cognitive/functional decline, and whether Alzheimer's disease (AD) pathology modifies these relationships. METHODSThe Pittsburgh Sleep Quality Index was administered to 326 older adults (113 cognitively normal, 192 mild cognitive impairment, 21 dementia; mean age = 66.4 ± 8.0 years) enrolled in the 1Florida Alzheimer's Disease Research Center. The Clinical Dementia Rating Sum of Boxes (CDR‐SB) assessed cognitive/functional decline at baseline and over time. Moderators included hippocampal volume (HV), amyloid beta (Aβ) positron emission tomography, and plasma phosphorylated tau (p‐tau)217. RESULTSCross‐sectionally, longer sleep duration and later wake time were associated with worse CDR‐SB, with stronger associations observed among individuals with higher Aβ and p‐tau217 levels, and smaller HV. Longitudinally, prolonged sleep duration was associated with faster cognitive decline, particularly in individuals with elevated Aβ or p‐tau217 levels and smaller hippocampal volumes at baseline. DISCUSSIONProlonged sleep duration and later wake times predicted worsening cognitive performance, and these effects were strengthened by greater AD pathology. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Text Encoded Conversion
  • XML
  • Save / Share this Record
  • Send to Email