The emergence of Aβ pathology is one of the hallmarks of Alzheimer’s disease (AD), but the mechanisms and impact of Aβ in progression of the disease is unclear. The nuclear pore complex (NPC) is a multi-protein assembly in mammalian cells that regulates movement of macromolecules across the nuclear envelope; its function is shown to undergo age-dependent decline during normal aging and is also impaired in multiple neurodegenerative disorders. Yet not much is known about the impact of Aβ on NPC function in neurons. Here, we examined NPC and nucleoporin (NUP) distribution and nucleocytoplasmic transport using a mouse model of AD (App^{NL-G-F/NL-G-F}) that expresses Aβ in young animals. Our studies revealed that a time-dependent accumulation of intracellular Aβ corresponded with a reduction of NPCs and NUPs in the nuclear envelope which resulted in the degradation of the permeability barrier and inefficient segregation of nucleocytoplasmic proteins, and active transport. As a result of the NPC dysfunction App KI neurons become more vulnerable to inflammation-induced necroptosis – a programmed cell death pathway where the core components are activated via phosphorylation through nucleocytoplasmic shutting. Collectively, our data implicates Aβ in progressive impairment of nuclear pore function and further confirms that the protein complex is vulnerable to disruption in various neurodegenerative diseases and is a potential therapeutic target.

Sequenced reactivations of hippocampal neurons called replays, concomitant with sharp-wave ripples in the local field potential, are critical for the consolidation of episodic memory, but whether replays depend on the brain’s reward or novelty signals is unknown. Here, we combined chemogenetic silencing of dopamine neurons in ventral tegmental area (VTA) and simultaneous electrophysiological recordings in dorsal hippocampal CA1, in freely behaving male rats experiencing changes to reward magnitude and environmental novelty. Surprisingly, VTA silencing did not prevent ripple increases where reward was increased, but caused dramatic, aberrant ripple increases where reward was unchanged. These increases were associated with increased reverse-ordered replays. On familiar tracks this effect disappeared, and ripples tracked reward prediction error (RPE), indicating that non-VTA reward signals were sufficient to direct replay. Our results reveal a novel dependence of hippocampal replay on dopamine, and a role for a VTA-independent RPE signal that is reliable only in familiar environments.