Faculty Bibliography

Although Down syndrome (DS) can be diagnosed prenatally, currently there are no effective treatments to lessen the intellectual disability (ID) which is a hallmark of this disorder. Furthermore, starting as early as the third decade of life, DS individuals exhibit the neuropathological hallmarks of Alzheimer's disease (AD) with subsequent dementia, adding substantial emotional and financial burden to their families and society at large. A potential therapeutic strategy emerging from the study of trisomic mouse models of DS is to supplement the maternal diet with additional choline during pregnancy and lactation. Studies demonstrate that maternal choline supplementation (MCS) markedly improves spatial cognition and attentional function, as well as normalizes adult hippocampal neurogenesis and offers protection to basal forebrain cholinergic neurons (BFCNs) in the Ts65Dn mouse model of DS. These effects on neurogenesis and BFCNs correlate significantly with spatial cognition, suggesting functional relationships. In this review, we highlight some of these provocative findings, which suggest that supplementing the maternal diet with additional choline may serve as an effective and safe prenatal strategy for improving cognitive, affective, and neural functioning in DS. In light of growing evidence that all pregnancies would benefit from increased maternal choline intake, this type of recommendation could be given to all pregnant women, thereby providing a very early intervention for individuals with DS, and include babies born to mothers unaware that they are carrying a fetus with DS.

Neuroplasticity involves molecular and structural changes in central nervous system (CNS) throughout life. The concept of neural organization allows for remodeling as a compensatory mechanism to the early pathobiology of Alzheimer's disease (AD) in an attempt to maintain brain function and cognition during the onset of dementia. The hippocampus, a crucial component of the medial temporal lobe memory circuit, is affected early in AD and displays synaptic and intraneuronal molecular remodeling against a pathological background of extracellular amyloid-beta (Abeta) deposition and intracellular neurofibrillary tangle (NFT) formation in the early stages of AD. Here we discuss human clinical pathological findings supporting the concept that the hippocampus is capable of neural plasticity during mild cognitive impairment (MCI), a prodromal stage of AD and early stage AD.

Down syndrome (DS) is caused by the triplication of human chromosome 21 (HSA21) and is the most common genetic cause of intellectual disability, with individuals having deficits in cognitive function including hippocampal learning and memory and neurodegeneration of cholinergic basal forebrain neurons, a pathological hallmark of Alzheimer's disease (AD). To date, the molecular underpinnings driving this pathology have not been elucidated. The Ts65Dn mouse is a segmental trisomy model of DS and like DS/AD pathology, displays age-related cognitive dysfunction and basal forebrain cholinergic neuron (BFCN) degeneration. To determine molecular and cellular changes important for elucidating mechanisms of neurodegeneration in DS/AD pathology, expression profiling studies were performed. Molecular fingerprinting of homogeneous populations of Cornu Ammonis 1 (CA1) pyramidal neurons was performed via laser capture microdissection followed by Terminal Continuation RNA amplification combined with custom-designed microarray analysis and subsequent validation of individual transcripts by qPCR and protein analysis via immunoblotting. Significant alterations were observed within CA1 pyramidal neurons of aged Ts65Dn mice compared to normal disomic (2N) littermates, notably in excitatory and inhibitory neurotransmission receptor families and neurotrophins, including brain-derived neurotrophic factor as well as several cognate neurotrophin receptors. Examining gene and protein expression levels after the onset of BFCN degeneration elucidated transcriptional and translational changes in neurons within a vulnerable circuit that may cause the AD-like pathology seen in DS as these individuals age, and provide rational targets for therapeutic interventions.

Endosomal-lysosomal and autophagic dysregulation occurs in the hippocampus in prodromal Alzheimer disease (AD), but its relationship with beta-amyloid (Abeta) and tau pathology remains unclear. To investigate this issue, we performed immunoblot analysis of hippocampal homogenates from cases with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment (MCI), and AD. Western blot analysis revealed significant increases in the acid hydrolase cathepsin D and early endosome marker rabaptin5 in the MCI group compared with AD, whereas levels of phosphorylated mammalian target of rapamycin proteins (pmTOR), total mammalian target of rapamycin (mTOR), p62, traf6, and LilrB2 were comparable across clinical groups. Hippocampal Abeta1-40 and Abeta1-42 concentrations and AT8-immunopositive neurofibrillary tangle density were not significantly different across the clinical groups. Greater cathepsin D expression was associated with global cognitive score and episodic memory score but not with mini mental state examination or advanced neuropathology criteria. These results indicate that alterations in hippocampal endosomal-lysosomal proteins in MCI are independent of tau or Abeta pathology.

Research indicates that female risk of developing Alzheimer's disease (AD) is greater than that of males. Moderate reduction of calorie intake, known as calorie restriction (CR), reduces pathology in AD mouse models and is a potentially translatable prevention measure for individuals at-risk for AD, as well as an important tool for understanding how the brain endogenously attenuates age-related pathology. Whether sex influences the response to CR remains unknown. In this study, we assessed the effect of CR on beta-amyloid peptide (Abeta) pathology and hippocampal CA1 neuron specific gene expression in the Tg2576 mouse model of cerebral amyloidosis. Relative to ad libitum (AL) feeding, CR feeding significantly reduced hippocampal Abeta burden in 15-month-old female, but not age-matched male, Tg2576 mice. Sustained CR also significantly reduced expression of presenilin enhancer 2 (Psenen) and presenilin 1, components of the gamma-secretase complex, in Tg2576 females. These results indicate that long-term CR significantly reduces age-dependent female Tg2576 Abeta pathology, which is likely to involve CR-mediated reductions in gamma-secretase-dependent amyloid precursor protein (APP) metabolism.

Objectives: Given that epidemiologic studies have shown that diabetes mellitus increases the risk of Alzheimer's disease (AD), our objective was to examine the mechanistic links between the two diseases in a non-human primate. Methods: Tissue from multiple brain regions of a vervet monkey model of streptozotocin-induced type 1 diabetes (n=10 control; n=7 diabetic) was examined by Western blot analysis, sandwich ELISA, and qPCR for biochemical changes in tau protein and Abeta peptide, as well as changes in key enzymes that contribute to their processing and posttranslational modification. Results: Regional brain analyses showed a global increase in tau phosphorylation in areas vulnerable to AD pathology as well as in spared structures such as the cerebellum. An examination of tau phosphatases and kinases showed a brain-wide increase in active ERK1/2. A diabetes-induced increase in Abeta levels, however, was specific to brain regions affected during the early stages of AD pathogenesis, with the greatest increase observed in the hippocampus. Examination of the amyloid precursor protein, its metabolites, and proteins involved in the clearance and degradation of brain Abeta indicated that a hippocampal-specific decrease in the Abeta-degrading enzyme neprilysin is a major contributor to this localized Abeta increase. Conclusions: Our study suggests protein changes in the brain that link diabetes to AD risk: decreased neprilysin expression leads to an increase in Abeta in the temporal lobe structures that are at the earliest risk in AD while increased ERK1/2 activity appears to contribute to a brain-wide increase in tau phosphorylation

Neurotrophins play a crucial role in mediating neuronal survival and synaptic plasticity. A lack of trophic factor support in the peripheral nervous system (PNS) is associated with a transcription-dependent programmed cell death process in developing sympathetic neurons. While most of the attention has been upon events culminating in cell death in the PNS, the earliest events that occur after trophic factor withdrawal in the central nervous system (CNS) have not been investigated. In the CNS, brain-derived neurotrophic factor (BDNF) is widely expressed and is released in an activity-dependent manner to shape the structure and function of neuronal populations. Reduced neurotrophic factor support has been proposed as a mechanism to account for changes in synaptic plasticity during neurodevelopment to aging and neurodegenerative disorders. To this end, we performed transcriptional profiling in cultured rat hippocampal neurons. We used a TrkB ligand scavenger (TrkB-FC ) to sequester endogenous neurotrophic factor activity from hippocampal neurons in culture. Using a high-density microarray platform, we identified a significant decrease in genes that are associated with vesicular trafficking and synaptic function, as well as selective increases in MAP kinase phosphatases. A comparison of these changes with recent studies of Alzheimer's disease and cognitive impairment in post mortem brain tissue revealed striking similarities in gene expression changes for genes involved in synaptic function. These changes are relevant to a wide number of conditions in which levels of BDNF are compromised. (c) 2014 Wiley Periodicals, Inc. Develop Neurobiol, 2014.

Down syndrome (DS) is the most prevalent cause of intellectual disability (ID). Individuals with DS show a variety of cognitive deficits, most notably in hippocampal learning and memory, and display pathological hallmarks of Alzheimer's disease (AD), with neurodegeneration of cholinergic basal forebrain (CBF) neurons. Elucidation of the molecular and cellular underpinnings of neuropathology has been assessed via gene expression analysis in a relevant animal model, termed the Ts65Dn mouse. The Ts65Dn mouse is a segmental trisomy model of DS which mimics DS/AD pathology, notably age-related cognitive dysfunction and degeneration of basal forebrain cholinergic neurons (BFCNs). To determine expression level changes, molecular fingerprinting of Cornu Ammonis 1 (CA1) pyramidal neurons was performed in adult (4-9 month old) Ts65Dn mice, at the initiation of BFCN degeneration. To quantitate transcriptomic changes during this early time period, laser capture microdissection (LCM), terminal continuation (TC) RNA amplification, custom-designed microarray analysis, and subsequent validation of individual transcripts by qPCR and protein analysis via immunoblotting was performed. Results indicate significant alterations within CA1 pyramidal neurons of Ts65Dn mice compared to normal disomic (2N) littermates, notably in the downregulation of neurotrophins and their cognate neurotrophin receptors among other classes of transcripts relevant to neurodegeneration. These results of this single population gene expression analysis at the time of septohippocampal deficits in a trisomic mouse model shed light on a vulnerable circuit that may cause the AD-like pathology invariably seen in DS that could help to identify mechanisms of degeneration, and provide novel gene targets for therapeutic interventions. J. Comp. Neurol., 2014. (c) 2014 Wiley Periodicals, Inc.