Within the overarching theme of """"""""Proteinopathies of the Aging Central Nervous System,"""""""" Project 5 has focused on Alzheimer's disease (AD). The insights we gained during the preceding funding period and the ever increasing threat AD poses to public health have motivated us to maintain this focus in the current proposal. We will also continue to utilize transgenic mice with neuronal expression of human amyloid precursor proteins (hAPP) and amyloid-p (A(3) peptides, because there is substantial evidence for mechanistically informative overlap between these models and the human condition. In our original application, we promised to shed light on the processes by which Ap elicits neuronal deficits. We found that neurons in the dentate gyrus and entorhinal cortex?brain regions affected early and severely by AD?are particularly vulnerable to the A|3-induced depletion of proteins that are critical for learning and memory. Several molecules were identified that may mediate this process. We also identified strategies to prevent A|3- induced neuronal deficits in hAPP mice. For example, reduction of the tau protein effectively prevented A(3- dependent memory deficits and molecular neuronal alterations. Although the mechanism underlying this striking rescue remains to be fully elucidated, we already know that it does not depend on changes in A(3 levels or deposition. Rather, tau reduction appears to prevent aberrant increases in neuronal network excitability. Our new proposal builds on the most promising findings we obtained during the preceding funding period.
In Aim 1, we will examine whether A|3 affects vulnerable neurons directly or indirectly through changes in other regions from which these neurons receive excitatory inputs.
In Aim 2, we will determine if the modulation of excitotoxicity-related neuronal or glial molecules can block Ap-induced neuronal overexcitation, eliminate aberrant network activities, and ameliorate behavioral abnormalities in hAPP mice.
In Aim 3, we will assess whether tau reduction can prevent neuronal deficits also in mouse models of Parkinson's disease and Huntington's disease. Confirmation of these untested hypotheses should help elucidate the mechanisms that underlie A|3-dependent cognitive deficits and pave the way for the development of better treatments for AD and other neurological disorders. The proposed studies involve collaborative interactions with all other project leaders and depend on support from all four cores. The mechanistic and therapeutic insights we will gain in this project should help answer some of the key questions pursued in the other projects and, thus, will benefit the program as a whole.
|Valera, Elvira; Spencer, Brian; Mott, Jennifer et al. (2017) MicroRNA-101 Modulates Autophagy and Oligodendroglial Alpha-Synuclein Accumulation in Multiple System Atrophy. Front Mol Neurosci 10:329|
|Valera, Elvira; Spencer, Brian; Fields, Jerel A et al. (2017) Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy. Acta Neuropathol Commun 5:2|
|Overk, Cassia; Masliah, Eliezer (2017) Perspective on the calcium dyshomeostasis hypothesis in the pathogenesis of selective neuronal degeneration in animal models of Alzheimer's disease. Alzheimers Dement 13:183-185|
|Spencer, Brian; Desplats, Paula A; Overk, Cassia R et al. (2016) Reducing Endogenous ?-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model. J Neurosci 36:7971-84|
|Spencer, Brian; Kim, Changyoun; Gonzalez, Tania et al. (2016) ?-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease. Hum Mol Genet 25:1100-15|
|Valera, Elvira; Masliah, Eliezer (2016) Therapeutic approaches in Parkinson's disease and related disorders. J Neurochem 139 Suppl 1:346-352|
|Spencer, Brian; Potkar, Rewati; Metcalf, Jeff et al. (2016) Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease. J Biol Chem 291:1905-20|
|Valera, E; Monzio Compagnoni, G; Masliah, E (2016) Review: Novel treatment strategies targeting alpha-synuclein in multiple system atrophy as a model of synucleinopathy. Neuropathol Appl Neurobiol 42:95-106|
|Valera, Elvira; Spencer, Brian; Masliah, Eliezer (2016) Immunotherapeutic Approaches Targeting Amyloid-?, ?-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders. Neurotherapeutics 13:179-89|
|Valera, Elvira; Masliah, Eliezer (2016) Combination therapies: The next logical Step for the treatment of synucleinopathies? Mov Disord 31:225-34|
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