IDENTIFICATION OF A MISSING KEY ELEMENT UNDERLYING APOE2 NEUROPROTECTION IN ALZHEIMER'S DISEASE AND THE AGING BRAIN

Aging is the strongest known risk factor for Alzheimer's disease (AD), the most common cause ofdementia in older individuals. However, effective AD therapies remain elusive, which underscores the need tobetter understand disease etiology and its co-occurrence with advanced age. Apolipoprotein E (apoE) is amajor lipid carrier in the brain that transports cholesterol and other lipids such as sulfatide (a key component ofmyelin) between brain cells. APOE polymorphic alleles are the main genetic determinants of AD risk (e.g.,APOE4 allele is the strongest genetic risk factor for AD). APOE alleles are also the major genetic determinantsof healthy aging and longevity (e.g., APOE2 is found at a high frequency among centenarians). Previousstudies from our group have shown that (1) sulfatide is exclusively transported by apoE particles in an isoform-dependent manner; (2) sulfatide content is specifically and dramatically reduced at the earliest clinicallyrecognizable stages in the brains of AD human subjects and animals; (3) sulfatide depletion in AD isaccelerated by amyloid beta; (4) brain sulfatide is regulated in an age dependent manner decreasing during oldage in both humans and rodents; (5) sulfatide-depleted mice display myelin and axonal abnormalities,extensive astrogliosis, and reduced lifespans; and (6) sulfatide mediates neuronal uptake of apoE. Thesefindings led us to hypothesize that apoE2 neuroprotective effects in the aging brain are driven by the capacityof apoE2 particles to carry less sulfatide content, compared to other isoforms, which consequently leads tohigher brain sulfatide levels and lower abilities to bind apoE receptors. To test this central hypothesis, wepropose three Specific Aims: 1) To investigate the association of brain apoE and lipid content from humanand mouse APOE2 and E3 carriers with neuroplasticity, markers of brain aging (white matter integrity andbrain atrophy), cognitive performance, and/or AD onset at different age groups; 2) To determine if sulfatide (orapoE) content affects neuroplasticity, white matter integrity, and cognitive performance in the aging mousebrain; and 3) To elucidate the molecular mechanism(s) by which brain sulfatide metabolism underlies theneuroprotective effects of apoE2 in AD and aging. To the best of our knowledge, the proposed research (inresponse to RFA-AG-18-022: ?Understanding the Effects of ApoE2 on the Interaction between Aging andAlzheimers Disease?) is the first to study the potential role of sulfatide in apoE2-mediated neuroprotection. Ifour hypothesis is borne out, this work may unravel the mechanism(s) by which apoE2 promotes healthy agingin the brain and lead to new therapeutic targets (i.e., sulfatide and the proteins involved in its metabolism) totreat AD and aging-related cognitive decline.