Normal axonal mitochondrial transport and function is essential for the maintenance of synaptic function by positioning mitochondria to their workplace; accordingly,damaged axonal mitochondrial motility results in synaptic functional perturbations including decreased synaptic activity and strength as well as defected synaptic plasticity.Recent studies have determined mitochondrial motility injury is a prominent pathology in Alzheimer s disease (AD) and is correlated to Amyloid beta (A β)-associated synaptic distress.However,the mechanisms controlling axonal mitochondrial function and transport alterations in AD remain elusive.Here,we report an unexplored role of cyclophilin D (CypD)-dependent mitochondrial permeability transition pore (mPTP) in A β-impaired axonal mitochondrial trafficking.Depletion of CypD significantly protects axonal mitochondrial motility and dynamics from A β toxicity as shown by increased axonal mitochondrial density and distribution and improved bidirectional transport of axonal mitochondria.Notably,blockade of mPTP by genetic deletion of CypDreverses A β-induced axonal mitochondrial abnormalities,improves synaptic function,and attenuates loss of synapse,suggesting the involvement of CypDin A β-induced alterations in axonal mitochondrial trafficking.These findings provide new insights into CypD-dependent mitochondfial mPTP and signaling on mitochondrial trafficking in axons and synaptic degeneration in an environment enriched for A β.