# Tau-PI3Kalpha Complex in Regulation of PI3K/Akt-dependent Neuronal Function and Survival

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $231,585

## Abstract

PROJECT SUMMARY
Tau pathologies including Alzheimer’s disease are the most prevalent and complex neurodegenerative diseases
of aging that will likely reach 115 million globally by 2050(6) yet, there are no therapeutic drugs to treat this
disease, except a controversial recently approved drug(7). Though the formation of intracellular neurofibrillary
tangles (NFTs) from the hyperphosphorylated tau protein in the cortical and hippocampal regions is a key
pathological hallmark of tau pathologies, the precise mechanisms of how hyperphosphorylated tau impact
survival signaling in neurons is lacking. Recently we have shown that the PI3K/Akt survival signaling
pathway is controlled by the non-neuronal type microtubule-associated protein 4 (MAP4) that directly interacts
with PI3K via its microtubule-binding domain (MTBD)(9). The PI3K interaction with MAP4 controls the PI3K
association with activated receptor kinases that are required for PI3K activation, PI3,4,5P3 generation, and
Akt activation(9). The MTBD of MAP4 that binds PI3K shows strikingly high homology with the microtubule-
binding domain of the neuronal microtubule-associated proteins tau and MAP2, stimulating the hypothesis that
tau and MAP2 substitute for MAP4 control of PI3K/Akt survival signaling in neurons. Our preliminary data shows
the association between tau and PI3K in primary neurons, induced pluripotent stem cells-derived neurons, and
a neuronal cell line. The siRNA-mediated knockdown of tau blocked insulin stimulated Akt activation.
We hypothesize that tau scaffold the PI3K along microtubules in axons and dendrites to control growth factor
stimulated PI3K/Akt survival signaling of neurons. Increased tau hyperphosphorylation and its aggregation
during Alzheimer’s disease progression impairs the spatial organization of PI3K along microtubules resulting
in loss of growth factor stimulated PI3K/Akt signaling that is critical for neuronal cell survival and function.
The focus of proposed study is to establish and understand mechanistically tau’s role in the PI3K/Akt signaling
and define the PI3K interaction sites in tau. The interaction between PI3K and tau will be used to define the
interaction sites for PI3K in the MTBD of tau and investigate if these sites coincide with pathogenic mutants
and hyperphosphorylation sites in the MTBD of tau. We will define the effect of tau loss on spatial distribution,
co-localization and interaction of PI3K with activated receptors in axons and dendrites, and effect on growth
factor stimulated PI3,4,5P3 generation and Akt activation. This will be further substantiated by a systemic
investigation of the impact of expressing mutant tau that is deficient on PI3K binding and the disruption of
PI3K-tau interaction by cell permeable peptides on spatial PI3K/Akt signaling and survival of neurons.

## Key facts

- **NIH application ID:** 10466209
- **Project number:** 1R21AG074605-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Richard A. Anderson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $231,585
- **Award type:** 1
- **Project period:** 2022-09-30 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466209

## Citation

> US National Institutes of Health, RePORTER application 10466209, Tau-PI3Kalpha Complex in Regulation of PI3K/Akt-dependent Neuronal Function and Survival (1R21AG074605-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10466209. Licensed CC0.

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