Abstract Background: AD presents with severe neurodegeneration which leads to cognitive deficits and dementia. While many previous approaches focused on targeting amyloid and/or tau, we identified a novel molecular and cellular target that attenuates neurodegeneration in AD which may be exploited as therapeutic targets.Methods: Using immunoblot, microscopic immunofluorescence and proteomic analysis, the current study revealed that PSAPP transgenic mice exhibit decreased hippocampal caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein that organizes synaptic signaling components. Subcellularly, Cav-1 and full length (fl)-TrkB were significantly decreased in hippocampal MLRs. We thus used viral vector that contains a neuronal-targeted Cav-1 construct using the synapsin promoter (SynCav1) to re-express Cav-1 in PSAPP mice. Effects of SynCav1 on cognition function, hippocampal neuron morphology and ultrastructure were examined at 9 (presymptomatic stage) and 11 month (symptomatic stage) respectively.Results: While PSAPP mice showed significant learning and memory deficits at 9 and 11 months, PSAPP mice that received hippocampal SynCav1 (PSAPP-SynCav1) maintained normal learning and memory at 9 and 11 months respectively. Furthermore, PSAPP-SynCav1 mice showed preserved hippocampal MLR-localized fl-TrkB, synaptic ultrastructure, dendritic arborization and axonal myelin content, all of which occurred independent of reducing amyloid deposit and astrogliosis.Conclusions: While transgenic PSAPP mice exhibit decreased hippocampal expression of the MLR scaffolding protein Cav-1 in the early stage of disease, SynCav1 mitigated neuropathology and cognitive deficits in PSAPP mice. Irrespective of amyloid, our approach targeted neuronal degeneration pathways that may be downstream of amyloid species and/or tau in AD but also other forms of neurodegeneration of different or unknown etiology.