Impairment of visual cortical plasticity by amyloid-beta species

NEUROBIOLOGY OF DISEASE

卷:154

Article

William, Christopher M.¹  Stern, Matthew A.³  Pei, Xuewei¹  Saqran, Lubna³  Ramani, Margish¹  Frosch, Matthew P.^2,3  Hyman, Bradley T.³ 

[1] NYU, Dept Pathol, Grossman Sch Med, 550 First Ave, New York, NY 10016 USA

[2] Massachusetts Gen Hosp, Neuropathol Serv, 114 16th St, Charlestown, MA 02129 USA

[3] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Neurol, 114 16th St, Charlestown, MA 02129 USA

关键词: Amyloid precursor protein (APP);    Amyloid-beta-40 (Aβ 40);    Aβ 42;    Alzheimer’ s disease;    Ocular dominance plasticity;    Visual cortex;    Synaptic plasticity;   

DOI  :  10.1016/j.nbd.2021.105344

来源: Elsevier

【 摘 要 】

Introduction: A variety of transgenic and knock-in mice that express mutant alleles of Amyloid precursor protein (APP) have been used to model the effects of amyloid-beta (A?) on circuit function in Alzheimer?s disease (AD); however phenotypes described in these mice may be affected by expression of mutant APP or proteolytic cleavage products independent of A?. In addition, the effects of mutant APP expression are attributed to elevated expression of the amyloidogenic, 42-amino acid-long species of A? (A?42) associated with amyloid plaque accumulation in AD, though elevated concentrations of A?40, an A? species produced with normal synaptic activity, may also affect neural function. Methods: To explore the effects of elevated expression of A? on synaptic function in vivo, we assessed visual system plasticity in transgenic mice that express and secrete A? throughout the brain in the absence of APP overexpression. Transgenic mice that express either A?40 or A?42 were assayed for their ability to appropriately demonstrate ocular dominance plasticity following monocular deprivation. Results: Using two complementary approaches to measure the plastic response to monocular deprivation, we find that male and female mice that express either 40- or 42-amino acid?long A? species demonstrate a plasticity defect comparable to that elicited in transgenic mice that express mutant alleles of APP and Presenilin 1 (APP/PS1 mice). Conclusions: These data support the hypothesis that mutant APP-driven plasticity impairment in mouse models of AD is mediated by production and accumulation of A?. Moreover, these findings suggest that soluble species of A? are capable of modulating synaptic plasticity, likely independent of any aggregation. These findings may have implications for the role of soluble species of A? in both development and disease settings.