# Preventing early events in Aβ-driven pathology in vivo

> **NIH NIH R01** · NATHAN S. KLINE INSTITUTE FOR PSYCH RES · 2021 · $404,250

## Abstract

PROJECT SUMMARY / ABSTRACT
An APP mutation identified in an Italian family that results in an amino acid substitution at position 2 of amyloid
β (AβIt) protects heterozygous carriers from AD even in advanced age. In vitro, AβIt prevents wild-type Aβ
(Aβwt) from forming Aβ amyloid fibrils and oligomerization, suggesting that co-expression of AβIt interferes with
Aβ nucleation and/or polymerization, a mechanism that is hypothesized to inhibit Aβ oligomerization,
amyloidogenesis and neurotoxicity in the heterozygous Italian APP (APPIt) carriers. In order to directly explore
the in vivo effect of this mutation we have generated a transgenic mouse overexpressing human APP with the
A673V Italian mutation under the control of Thy1.2 promoter sequences (TgAPPIt mice). We will investigate
the anti-amyloidogenic effect of AβIt when co-expressed with the human Aβwt in vivo using amyloid-depositing
mice (APP23) crossed with the TgAPPIt mice (Aim 1). Examining mechanism within the brain, we will
determine whether AβIt protection is due to the inhibition of Aβ nucleation or due to enhanced Aβ degradation,
decreased oligomer/early aggregate stability, and/or enhanced clearance of the AβIt/Aβwt interacting peptides,
testing the hypothesis that the amino-terminally mutated AβIt interferes with the earliest events necessary for
the initiation of β amyloid-driven pathology. In an initial therapeutic strategy, the anti-amyloidogenic function of
AβIt will be investigated by administering to amyloid depositing mice exosomes-enriched extracellular vesicles
(EV) as a source of AβIt (Aim 2). In part because of their stability, autologous EV have many appealing
properties as peptide, protein, and RNA delivery tools, and we have shown that brain EV contain APP, are
highly enriched with APP carboxyl-terminal fragments (APP-CTFs) and are therefore a source of EV-generated
Aβ. In preliminary studies we used our novel technique to isolate EV from the brain extracellular space of
TgAPPIt mice and administered these intranasally to amyloid depositing mice. Amyloid deposition was reduced
in mice treated with brain-derived EV from TgAPPIt mice compared to mice treated with EV isolated from the
brain of wild-type mice, supporting our hypothesis that AβIt interferes with developing Aβ pathology and
supporting our idea that EV can be used to deliver protective constituents to the brain. TgAPPIt brain-derived
EV will be delivered prior to amyloid deposition and at an age when amyloid deposition is abundant, and
recipient mice will be examined for Aβ oligomerization, amyloid deposition, neuronal loss and behavioral
deficits. We will further examine the anti-amyloidogenic potential and protective effects of AβIt using EV loaded
with APP-A673V mRNA or AβIt peptides, as well as a non-fibrillogenic peptide comprised of the 6 amino-
terminal residues of AβIt. These studies are timely, given the growing interest in developing EV as therapeutic
vehicles for both systemic and brain disorders, ...

## Key facts

- **NIH application ID:** 10147836
- **Project number:** 5R01AG056732-05
- **Recipient organization:** NATHAN S. KLINE INSTITUTE FOR PSYCH RES
- **Principal Investigator:** EFRAT LEVY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,250
- **Award type:** 5
- **Project period:** 2017-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147836

## Citation

> US National Institutes of Health, RePORTER application 10147836, Preventing early events in Aβ-driven pathology in vivo (5R01AG056732-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10147836. Licensed CC0.

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