Amyloid precursor protein and presenilin-1 knock-in immunodeficient mice exhibit intraneuronal Aβ pathology, microgliosis, and extensive neuronal loss.

INTRODUCTION

Transgenic mice overexpressing familial Alzheimer's disease (AD) mutations (FAD) show non-physiological traits, and their immunocompetent backgrounds limit their use in AD immunotherapy research. Preclinical models that reflect human immune responses in AD are needed.

METHODS

Using CRISPR-Cas9, we developed single (NA) and double (NAPS) knock-in (KI) amyloid precursor protein (APP)KM670,671NL (Swedish) and presenilin 1 (PS 1)M146VFAD mutations on an immunodeficient NOG (NOD.Cg-PrkdcscidIl2rgtm1Sug/JicTac) background. The models were confirmed by Sanger sequencing and evaluated for AD-like pathology.

RESULTS

Both NA and NAPS mice developed pathology without overexpression artifacts. Mutation-induced upregulation of APP-CTF-β led to intraneuronal human amyloid beta (Aβ) (6E10) deposits and amyloid-associated microgliosis as early as 3 months, which increased with age. The addition of the PS 1M146V mutation doubled the amyloid load. The models displayed broad neuronal loss, resulting in brain atrophy in older mice.

DISCUSSION: These models replicate intraneuronal amyloid pathology and, with human immune reconstitution potential, enable novel studies of human immune responses in AD.

HIGHLIGHTS: A novel Alzheimer's disease (AD) knock-in (KI) mouse was developed and characterized on an immunodeficient NOG background. The model provides a platform for human immune studies and the evaluation of immunotherapies for AD. The KI mice demonstrate intraneuronal Aβ deposits and amyloid-associated microglial reactions. KI mice demonstrate extensive neuronal loss. Human immune reconstitution enables studies of infectious AD co-morbidities, such as the human immunodeficiency and herpes simplex viruses.