A PS1 mutation linked to familial Alzheimer's disease induces neurodevelopmental abnormalities in forebrain

Abstract

Alzheimer's disease (AD) is a devastating condition that accounts for the majority of dementia cases. However, the precise temporal and spatial evolution of neuropathological alterations remains unresolved. Studies examining the function of presenilin 1 (PS1), the main gene responsible for familial AD (FAD), have led to experimental observations implicating the gene in regulating forebrain development. Our hypothesis is that an FAD-linked mutation in PS1 (PS1 M146V KI) may disrupt neurogenesis during forebrain development by limiting the potential of regional stem cells to give rise to the proper complement of neuronal or glial progeny.;PS1KI mice exhibited selective deregulation of medial ganglionic eminence (MGE) transcription factor expression profiles associated with GABAergic neuronal specification. These alterations coincided with enhanced elaboration of calbindin and calretinin GABAergic subtypes as well as reduced expression of the GABAergic migratory factor, Dlx2. Moreover, BrdU incorporation studies demonstrated alterations in the profiles of progenitor cells exiting the cell cycle in PS1KI mice. Additionally, stem cell self-renewal potential was compromised.;Analysis of dorsal forebrain/neocortex demonstrated reduced expression of the transcription factor Coup-TF1 as well as the expression of the transcript for ER81, a biomarker of presumptive layer V neurons. These results indicate that the developmental timing of neocortical specification as well as laminar formation and cortical density are altered and potentially delayed in PS1KI mice.;Gene microarray analysis of forebrain sub-domains at E12.5 exhibited unique and selective regional gene disruption. In MGE, Sox3, a novel target involved in mediating neuronal differentiation, was disrupted in PS1KI mice. Furthermore, increased expression of Notch and selective downstream pathway target genes were observed both in ventral and dorsal forebrain beginning at E12.5 and peaking at E15.5.;In summary, our cumulative experimental findings demonstrate that an FAD-linked PS1 mutation is capable of altering the normal course of embryonic and perinatal forebrain development by perturbing neurogenic cues along with disruptions of cell cycle kinetics and neural subtype identity. The potential implications of these findings may require a paradigm shift in our thinking about the pathogenesis of AD and the early developmental antecedents of the late-onset neurodegeneration.