Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury

• APP and the APP secretase proteins, Bace1 and PS1, accumulate acutely after SCI in mice.
• This is a functional accumulation which leads to the production of Aβ peptide at the injury site.
• Inhibiting Aβ production by targeting the APP secretases results in greater impaired functional recovery after SCI.
• Aβ may have a beneficial role after SCI.

Amyloid-β (Aβ) is produced through the enzymatic cleavage of amyloid precursor protein (APP) by β (Bace1) and γ-secretases. The accumulation and aggregation of Aβ as amyloid plaques is the hallmark pathology of Alzheimer׳s disease and has been found in other neurological disorders, such as traumatic brain injury and multiple sclerosis. Although the role of Aβ after injury is not well understood, several studies have reported a negative correlation between Aβ formation and functional outcome. In this study we show that levels of APP, the enzymes cleaving APP (Bace1 and γ-secretase), and Aβ are significantly increased from 1 to 3 days after impact spinal cord injury (SCI) in mice. To determine the role of Aβ after SCI, we reduced or inhibited Aβ in vivo through pharmacological (using DAPT) or genetic (Bace1 knockout mice) approaches. We found that these interventions significantly impaired functional recovery as evaluated by white matter sparing and behavioral testing. These data are consistent with a beneficial role for Aβ after SCI.