Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) pathology and
is closely linked to oxidative stress, which contributes to blood–brain barrier leakage,
renal dysfunction, and cognitive decline. We investigated the effects of N-acetyl cysteine
(NAC), an FDA-approved antioxidant, on oxidative stress, brain Aβ levels, barrier leakage,
renal function, and cognition in 5xFAD mice. Eight-week-old 5xFAD mice were fed a
rodent diet supplemented with 600 mg/kgDiet NAC for 4 weeks; wild-type (WT) mice
and control 5xFAD mice were fed a regular rodent diet. We detected elevated brain and
renal 4-hydroxynonenal(4-HNE) levels, reduced creatinine clearance, and increased plasma
S100β levels in untreated 5xFAD mice compared to WT controls. Untreated 5xFAD mice
also had higher capillary leakage, reduced P-gp activity, and impaired cognition compared
to WT. NAC treatment of 5xFAD mice reduced brain Aβ40 levels, normalized 4-HNE
levels to control levels, improved creatinine clearance, decreased capillary leakage, and
lowered S100β plasma levels. NAC improved cognitive performance in 5xFAD mice, as
shown by Y-maze. Our findings indicate that Aβ-induced oxidative stress contributes to
barrier dysfunction, renal impairment, and cognitive deficits in 5xFAD mice. Notably, NAC
treatment mitigates these effects, suggesting its potential as an adjunct therapy for AD and
other Aβ-related pathologies by reducing oxidative stress.
