# Structural characterization of APP family proteins

> **NIH NIH R03** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $157,000

## Abstract

Project Summary/Abstract
Alzheimer disease (AD) is a neurodegenerative disease characterized by progressive decline of brain
functions, progressive loss of synapses, neuronal death, brain atrophy and formation of extracellular amyloid
plaques and intracellular neurofibrillary tangles. The amyloid precursor protein (APP) is a type I
transmembrane glycoprotein which plays a central role in AD pathogenesis, as the precursor of the beta
amyloid peptide (Aβ), the main component of amyloid plaques. In addition, several mutations on the APP
gene are associated with the early-onset hereditary form of the disease (Familial Alzheimer disease or FAD).
Apart from being the precursor of the toxic Aβ peptide and the carrier of FAD mutations, APP has been
associated with a wide range of biological functions, including proliferation, neuronal development,
intracellular transport, Ca2+ homeostasis, neurite outgrowth, shaping of dendritic complexity and, most
importantly, synaptogenesis and synaptic function. Indeed, multiple reports link APP to the regulation of spine
density, spine dynamics and synaptic plasticity. Reported synaptic roles of APP both in the presynaptic active
zone and postsynaptic density include regulation of presynaptic nicotinic receptors, facilitation of
neurotransmitter release, regulation of synaptic vesicle recycling and regulation of the cell surface expression
and activity of NMDA receptors. Deregulation of one or more of the above functions is therefore likely to lead
to synaptic dysfunction and neurodegeneration, also basic hallmarks of the AD. APP is part of a gene family,
with two more mammalian members, the Amyloid Precursor Like Protein 1 (APLP1) and the Amyloid
Precursor Like Protein 2 (APLP2). Both APLPs are highly homologous to APP, with similar molecular
architecture and functions, especially related to synaptogenesis, spine dynamics and synaptic plasticity. The
goal of this proposal is to develop suitable experimental resources for performing structural investigations of
the physiological functions of APP and APLPs. To achieve this goal, we propose to establish an expression
and purification pipeline for medium throughput screening of APP, APLP1 and APLP2 orthologs, investigate
an alternative tagging procedure and compare extraction and reconstitution methods for a subset of orthologs.
Finally, we propose to utilize single particle cryo-electron microscopy (cryoEM) to elucidate atomic-level
details of the molecular architecture of APP family proteins. High-resolution structural information of a full-
length APP family protein will enable us to better understand the structural basis of the physiological functions
of APP and APP-like proteins and inform our understanding of how these functions are deregulated in AD.

## Key facts

- **NIH application ID:** 10815785
- **Project number:** 5R03AG081787-02
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Vasileios I Petrou
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $157,000
- **Award type:** 5
- **Project period:** 2023-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815785

## Citation

> US National Institutes of Health, RePORTER application 10815785, Structural characterization of APP family proteins (5R03AG081787-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10815785. Licensed CC0.

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