Alzheimer＇s　disease　(AD)　is　one　of　the　most　devastating　neurodegenerative　disorders.　Intracellular　beta-amyloid　protein　(A　beta)　is　an　early　event　in　AD.　It　induces　the　formation　of　amyloid　plaques　and　neuron　damage.　The　alpha　7　nicotinic　acetylcholine　receptor　(alpha　7nAChR)　has　been　suggested　to　play　an　important　role　in　A　beta　caused　cognition.　It　has　high　affinity　with　A　beta　and　could　mediate　A　beta　internalization　in　vitro.　However,　whether　in　mouse　brain　the　p38　MAPK　signaling　pathway　is　involved　in　the　regulation　of　the　alpha　7nAChR　mediated　A　beta　internalization　and　their　role　in　mitochondria　remains　little　known.　Therefore,　in　this　study,　we　revealed　that　A　beta　is　internalized　by　cholinergic　and　GABAergic　neurons.　The　internalized　A　beta　were　found　deposits　in　lysosomes/endosomes　and　mitochondria.　A　beta　could　form　A　beta-alpha　7nAChR　complex　with　alpha　7nAChR,　activates　the　p38　mitogen　activated　protein　kinase　(MAPK).　And　the　increasing　of　alpha　7nAChR　could　in　return　mediate　A　beta　internalization　in　the　cortex　and　hippocampus.　In　addition,　by　using　the　alpha　7nAChR　agonist　PNU282987,　the　p38　phosphorylation　level　decreases,　rescues　the　biochemical　changes　which　are　tightly　associated　with　A　beta-induced　apoptosis,　such　as　Bcl2/Bax　level,　cytochrome　c　(Cyt　c)　release.　Collectively,　the　p38　MAPK　signaling　pathway　could　regulate　the　alpha　7nAChR-mediated　internalization　of　A　beta.　The　activation　of　alpha　7nAChR　or　the　inhibition　of　p38　MAPK　signaling　pathway　may　be　a　beneficial　therapy　to　AD.