# Tau-dependent cognitive deficits in alpha-synucleinopathies

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $550,840

## Abstract

Summary/Abstract:
 Parkinson’s disease (PD) is the second most common late-onset neurodegenerative disease
with the largest relative increase in mortality rates among all neurological disorders. PD is
traditionally considered a motor disorder, characterized by the loss of dopaminergic neurons of
the SNpc, and the presence of fibrillar cytoplasmic inclusions called Lewy bodies and Lewy
neurites. However, a more global perspective on the PD is developing, motivated by pathological
and clinical findings that extend beyond the basal ganglia. In particular, the majority of PD patients
meet criteria for a secondary diagnosis of mild cognitive impairment that progresses dementia, a
significant contributor to disease morbidity and mortality. The emerging view is that the
abnormalities in α-synuclein (αS) may be responsible for motor and non-motor symptoms in PD
and Dementia with Lewy Bodies (DLB). Significantly, we recently found that abnormal αS can
cause post-synaptic deficits in vitro and in vivo via a microtubule associated protein tau (MAPT)
dependent mechanism. In this proposal, we will directly determine the following hypothesis: 1)
Pathogenic αS species produce cognitive decline tau-dependent post-synaptic mechanisms and
2) MAPT-dependent postsynaptic deficits caused by exogenous αS fibrils/oligomers contribute to
cognitive deficits in sporadic PD and DLB. To determine the mechanistic basis for cognitive
deficits in α-synucleinopathy, we propose following aims: 1) Determine whether tau is required
for αS dependent synaptic and cognitive deficits; 2) Determine if mutant αS-dependent AMPAR
deficits and memory deficits are caused by multiple pathways; 3) Determine whether hippocampal
αS pathology and somatodendritic tau mislocalization correlates with dementia in PD; 4)
Determine if exogenous pathogenic αS induces pre- and/or post-synaptic deficits; and 5)
Determine if pathogenic αS induces defects in synaptic plasticity and memory in a tau dependent
manner.

## Key facts

- **NIH application ID:** 10112975
- **Project number:** 5R01NS108686-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Alfonso Araque
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $550,840
- **Award type:** 5
- **Project period:** 2018-05-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112975

## Citation

> US National Institutes of Health, RePORTER application 10112975, Tau-dependent cognitive deficits in alpha-synucleinopathies (5R01NS108686-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112975. Licensed CC0.

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