Abstract
Alzheimer disease (AD) is characterized by cognitive impairment that starts with memory loss to end in dementia. Loss of synapses and synaptic dysfunction are closely associated with cognitive impairment in AD patients. Biochemical and pathological evidence suggests that soluble Aβ oligomers correlate with cognitive impairment. Here, we used the TgCRND8 AD mouse model to investigate the role of JNK in long term memory deficits. TgCRND8 mice were chronically treated with the cell-penetrating c-Jun N-terminal kinase inhibitor peptide (D-JNKI1). D-JNKI1, preventing JNK action, completely rescued memory impairments (behavioral studies) as well as the long term potentiation deficits of TgCRND8 mice. Moreover, D-JNKI1 inhibited APP phosphorylation in Thr-668 and reduced the amyloidogenic cleavage of APP and Aβ oligomers in brain parenchyma of treated mice. In conclusion, by regulating key pathogenic mechanisms of AD, JNK might hold promise as innovative therapeutic target.
Highlights
Neuropathological mechanisms in Alzheimer disease (AD) are partially unknown
Alzheimer disease (AD) is characterized by cognitive impairment that starts with memory loss to end in dementia
JNK Regulates Pathological Form of A in TgCRND8 Mouse Brains—Because the accumulation of A peptides, derived via amyloid precursor protein (APP) processing, is responsible for memory decline as well as for synaptic dysfunction [3, 7, 8, 32], we investigated the effect of D-JNKI1 in TgCRND8 mice focusing on the processing of APPSw/In linked to familial AD
Summary
Results: Chronic JNK inhibition with a cell-permeable peptide (CPP) rescues memory deficits, LTP impairment, and reduces A oligomers in a mouse model that mimics AD. D-JNKI1, preventing JNK action, completely rescued memory impairments (behavioral studies) as well as the long term potentiation deficits of TgCRND8 mice. Alzheimer disease (AD) is a progressive neurodegenerative disorder that begins with episodic short term memory deficits [1] and culminates with long term memory impairment and total loss of cognitive functions. JNK inhibition was achieved by treating TgCRND8 mice with the cell-penetrating inhibitor peptide, D-JNKI1 [23, 24], which, to date, represents the most specific JNK inhibitor available. We showed for the first time that chronic treatment with D-JNKI1 rescues cognitive dysfunction, memory impairment, and LTP in TgCRND8 mice. It modulates APP processing leading to inhibition of toxic soluble A production without any major side effects
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
