Alzheimers disease(AD) is a progressive neurodegenerative disorder that affects the elderly. Clinical studies have found that the amyloid deposits in the brain are aggravated along with the deterioration of the AD pathology. Indeed,Aβ peptides change particularly significantly early in the preclinical stage,and then detection of Aβ is of great importance in early diagnosis. Therefore,it is critical to diagnose and treat AD at the preclinical stage,and Aβ becomes the key target of intational research. We also focus on risk factors for preclinical Alzheimers disease,especially imbalance in lipid metabolism. Our current study presented a novel model with early onset of cognitive dysfunction by phospholipid transfer protein(PLTP) deficiency in APP/PS1ΔE9 mice without appearance of amyloid deposition. Dysfunction of PLTP might be a risk factor for the elevated Aβ in the preclinical stage of AD. We first found several potential functions of PLTP deficiency in the AD model mice:impairing cognitive performance;involvement in APP trafficking/processing and intracellular Aβ generation;inducing Aβ42 related alteration of BDNF. These established PLTP deficient AD mouse models could provide insights to early stages in AD like mild cognitive impairment(MCI) or preclinical AD(PCAD). Lipoprotein lipase(LPL) is expressed at high levels in hippocampal neurons,although its function is unclear. Lipoprotein lipase(LPL) is expressed at high levels in hippocampal neurons, although its function is unclear. We previously reported that LPL-deficient mice have leing and memory impairment and fewer synaptic vesicles in hippocampal neurons,but properties of synaptic activity in LPL-deficient neurons remain unexplored. In this study,we found reduced frequency of miniature excitatory postsynaptic currents(mEPSCs) and readily releasable pool(RRP) size in LPL-deficient neurons,which led to presynaptic dysfunction and plasticity impairment without altering postsynaptic activity. We demonstrated that synaptic vesicle recycling,which is known to play an important role in maintaining the RRP size in active synapses,is impaired in LPL-deficient neurons. Moreover,lipid assay revealed deficient docosahexaenoic acid(DHA) and arachidonic acid(AA) in the hippocampus of LPL-deficient mice;exogenous DHA or AA supplement partially restored synaptic vesicle recycling capability. These results suggest that impaired synaptic vesicle recycling results from defi cient DHA and AA and contributes to the presynaptic dysfunction and plasticity impairment in LPL-defi cient neurons. Accumulating evidence supported thatα-synuclein(α-syn) and ubiquitin C-terminal hydrolase L1(UCHL1) are required for normal synaptic and cognitive function. In this study,we found thatα-syn aggregated and the expression of UCHL1 decreased in the brain of LPL defi cient mice. Reduction of UCHL1 was resulted from nuclear retention of DNA cytosine-5-methyltransferase 1 in LPL knockout mice. Reverse changes were found in cultured cells overexpressing LPL. Furthermore,defi ciency of LPL increased ubiquitination ofα-syn. These results indicated that aggregation ofα-syn and reduction of UCHL1 expression in LPL-defi cient mice may affect synaptic function.