This supplemental grant proposal is for the currently funded RO1, ?Genetic Dissection of Catecholaminergic Innervation of the Cognitive Cerebellum.? Work derived from this grant so far has implicated an noradrenergic projection circuit from the Locus Ceruleus (LC) to the dentate or lateral nucleus of the cerebellum (LCN) in mice as a locus modulating several cognitive behaviors affected by dementias such as Alzheimer's Disease, including working memory, response inhibition, associative learning of fear, and behavioral flexibility. We propose to interrogate the role of this circuit in order to understand tauopathies such as Alzheimer's Disease. Tauopathies are a group of progressive neurodegenerative disorders with no known disease modifying treatments. Tauopathies include a range of illnesses, including Alzheimer's disease (AD), Chronic Traumatic Encephalopathy (CTE) from traumatic brain injury, some frontotemporal dementias (FTD), and progressive supranuclear palsy (PSP). These illnesses are associated with cognitive dysfunction, neuropsychiatric symptoms, and collectively affect millions of Americans, causing significant morbidity and mortality. The cerebellum has different pathological patterns in these illnesses: in Alzheimer's disease, cerebellar tau deposition and cell death is seen in early onset and familial cases, whereas tau deposition and cell death in cerebellum is commonly seen in CTE, PSP and FTD. While a global effort to cure tauopathies is underway, it is estimated that merely suppressing or delaying the clinical expression of the particular tauopathy, AD, by half could lower the prevalence of dementia by ~80% because of its exponential relationship to age. The deposition of tau is a pathophysiological process that drives both synaptic and neuronal cell loss, leading to cognitive dysfunction. The essential neuropathologic changes of AD are the accumulation of ?- amyloid (A?) peptides and hyperphosphorylated paired-helical filament (PHF)-? containing neurofibrillary tangles. The distribution of A? and PHF-? accumulation follows distinct stereotypic patterns across brain regions as AD advances and this pattern seems core to AD pathogenesis. It is also now clear that there is progressive degeneration and neuropathologic changes in subcortical regions of the AD brain. A? and PHF-? deposition in the cerebellum is involved in AD cases with earlier disease onset and greater clinical penetrance. While LC degeneration has long been implicated in the pathogenesis of AD and LC is one of the first brain regions to develop PHF-? containing neurofibrillary tangles, very little is known about the influence of PHF-? in the LC on cognitive cerebellar function in AD or PSP. We hypothesize that tau pathology has direct and indirect effects on the cerebellum that contribute to cognitive impairment. We will interrogate the pathological and behavioral consequences with manipulations: first, we will characterize involvement of a LC->LCN circuit in a known mouse model of tauopathy, the P301L mouse line, and second, we will characterize the pathological and behavioral consequences of expressing hyperphosphorylated paired-helical filament (PHF)-? in two regions: LC and LCN.
Degeneration of the catecholaminergic Locus Ceruleus (LC) has long been implicated in the pathogenesis of Alzheimer's disease (AD), and it is one of the first regions to accumulate pathological forms of tau protein. Furthermore, alterations in cerebellar function contribute to cognitive deficits in many neuropsychiatric diseases and are increasingly recognized in AD. How distinct LC projection circuits, particularly to cognitive areas in the cerebellum, contribute to cognitive dysregulation in AD is poorly understood, but likely contributes to the etiology of many AD symptom domains. We will use advanced genetic and behavioral techniques to target the cognitive cerebellar cortex and the catecholaminergic innervation of the dentate (or lateral) nucleus of the cerebellum and determine how these circuits contribute to behavioral domains relevant to AD.
