amyloid-beta-peptides and Movement-Disorders

Ubiquilin-1 (Ubqln1) is a ubiquitin-like protein that has been implicated in Alzheimer's disease (AD). However, whether Ubqln1 modulates learning and memory and alters AD-like behavior and/or pathology has not been determined in animal models. To understand the function of Ubqln1 in vivo, we previously generated Ubqln1 transgenic (TG) mice that overexpress mouse Ubqln1. With the model, we here characterized the TG mouse cognitive behaviors and found that Ubqln1 TG mice showed better spatial learning and memory capabilities than their wild-type littermates in both radial arm water maze and Y-maze tests. Additionally, we crossed the Ubqln1 TG mice with the AβPPswe/PSEN1dE9 double transgenic AD mouse to generate the AD/Ubqln1 triple TG (AD/TG) mice. Our results suggest that at 12 months of age following the onset of AD, AD/TG mice showed better spatial learning and memory than AD mice. AD/TG mice also exhibited better motor function than AD mice at the same age. Furthermore, compared to AD mice, AD/TG mice showed significant reduction in amyloid-β 40 (Aβ40) and Aβ42 levels in the cerebral cortex and in the hippocampus at the post-onset stage. The number of Aβ plaques was significantly decreased in the cerebral cortex of AD/TG mice at this post-onset stage. Moreover, mature AβPP level in AD/TG hippocampus was lower than that in AD hippocampus. These data not only provide a direct link between overexpression of Ubqln1 and altered learning and memory, but also raise the possibility that Ubqln1 is a potential therapeutic target for treating AD and possibly other neurodegenerative disorders.

Topics: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Autophagy-Related Proteins; Brain; Cognition Disorders; Disease Models, Animal; Gene Expression Regulation; Hand Strength; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Movement Disorders; Mutation; Peptide Fragments; Presenilin-1; Rotarod Performance Test

Apolipoprotein E (ApoE) has an active part in the pathogenesis of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) and plasma level alterations have been reported in AD patients. In search of a biomarker potentially predictive of cognitive, functional, or motor decline, we analyzed the CSF to serum ratios of ApoE levels (CSF/serum ApoE) in AD patients in this regard.. Subjects with newly diagnosed AD were followed within a longitudinal observational study (rpAD study). Annual neuropsychological testing and physical examination were performed. Multiple regression analyses were used to determine possible associations of the ApoE CSF/serum concentration ratios and velocity of decline on a variety of cognitive, functional and motor scales (MMSE, iADL, bADL, GDS, UPDRSIII) adjusted for relevant co-variables.. CSF/serum ratios of ApoE levels were associated with progression on the UPDRSIII (change of UPDRSIII slope [pt/yr] per unit of ApoE CSF/serum = -0.06, p <  0.01) and instrumental ADL scale (change of iADL slope [pt/yr] per unit of ApoE CSF/serum = 0.01, p = 0.01) ("the lower the ratio, the faster the deterioration" and vice versa). Secondarily, higher age at onset was associated with faster UPDRSIII progression, antidepressant use with faster iADL decline, and better baseline function with more rapid decline on either MMSE, iADL, or GDS scale.. Here, CSF/serum ApoE at time of AD diagnosis was shown to be inversely associated with medium-term functional and motor progression. Whether this ratio qualifies for the use as a predictive biomarker must be validated in larger cohort studies over the long term.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Cognition Disorders; Female; Humans; Longitudinal Studies; Male; Mental Status Schedule; Middle Aged; Movement Disorders; Peptide Fragments; Severity of Illness Index; tau Proteins

Traumatic brain injury (TBI) is a recognized risk factor for later development of neurodegenerative disease. However, the mechanisms contributing to neurodegeneration following TBI remain obscure.. In this study, we have utilized a novel mild TBI (mTBI) model to examine the chronic neurobehavioral and neuropathological outcomes following single and repetitive mTBI at time points from 6 to 18 months following injury.. Our results reveal that at 6, 12, and 18 months after injury, animals exposed to a single mTBI have learning impairments when compared to their sham controls without exhibiting spatial memory retention deficits. In contrast, animals exposed to repetitive injury displayed persistent cognitive deficits, slower rate of learning, and progressive behavioral impairment over time. These deficits arise in parallel with a number of neuropathological abnormalities, including progressive neuroinflammation and continuing white matter degradation up to 12 months following repetitive injury. Neither single nor repetitive mTBI was associated with elevated brain levels of amyloid beta or abnormal tau phosphorylation at 6 or 12 months after injury.. Importantly, these data provide evidence that, although a single mTBI produces a clinical syndrome and pathology that remain static in the period following injury, repetitive injuries produce behavioral and pathological changes that continue to evolve many months after the initial injuries. As such, this model recapitulates many aspects described in human studies of TBI, providing a suitable platform on which to investigate the evolving pathologies following mild TBI and potential strategies for therapeutic intervention.

Topics: Amyloid beta-Peptides; Animals; Anxiety; Brain Injuries; Cognition Disorders; Corpus Callosum; Disease Models, Animal; Gene Expression Regulation; Male; Maze Learning; Mice; Mice, Inbred C57BL; Movement Disorders; Nerve Fibers, Myelinated; Peptide Fragments; Retention, Psychology; Rotarod Performance Test; tau Proteins; Time Factors