# Elucidating the role of Locus Coeruleus projections to the Cognitive Cerebellum in mouse models of Alzheimer's Disease (Administrative Supplement)

> **NIH NIH R01** · SEATTLE INST FOR BIOMEDICAL/CLINICAL RES · 2020 · $334,708

## Abstract

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 β-
amyloid (Aβ) peptides and hyperphosphorylated paired-helical filament (PHF)-τ containing neurofibrillary
tangles. The distribution of Aβ and PHF-τ 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. Aβ and PHF-τ
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-τ containing neurofibrillary tangles, very little is known about the influence of PHF-τ 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 kno...

## Key facts

- **NIH application ID:** 10118991
- **Project number:** 3R01MH116883-03S1
- **Recipient organization:** SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
- **Principal Investigator:** Erik Sean Carlson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $334,708
- **Award type:** 3
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118991

## Citation

> US National Institutes of Health, RePORTER application 10118991, Elucidating the role of Locus Coeruleus projections to the Cognitive Cerebellum in mouse models of Alzheimer's Disease (Administrative Supplement) (3R01MH116883-03S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10118991. Licensed CC0.

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