The Genesis of Region-specific White Matter Deficits During Early Alzheimer's Disease Pathogenesis

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to memory and cognitive impairment. thereby affecting the activities of daily living and behavior in an estimated 5.3 million Americans of all ages. Pathologically, AD is characterized by the temporal and spatial progression of amyloid plaques from deposition of the fibrillogenic Abeta peptide, neurofibrillary tangles from hyperphosphorylation of the microtubule stabilizing protein tau, decreased synaptic density, and eventual neuronal loss. AD has not been widely considered as a white matter disease, but more recent evidence suggests the existence of abnormalities in myelination patterns and myelin attrition in AD-afflicted human brains, implying that oligodendrocytes, the cellular components that comprise myelin, may be affected in the CNS of AD patients. Oligodendrocytes have been shown to be sensitive to Abeta-induced toxicity, oxidative stress, and inflammatory cytokines. We hypothesized that oligodendrocytes represent a susceptible cell population targeted at the earliest of stages in AD pathogenesis in a predictive triple-transgenic (3xTg-AD) mouse model of AD. Moreover, the use of disease-modifying interventions would attenuate spatial and temporal advancement of axonal dysmyelination in 3xTg-AD mice.;We initially assessed white matter homeostasis in 3xTg-AD mice, which harbor the human amyloid precursor protein Swedish mutant (hAPPswe ) transgene, presenilin knock-in mutation (hPS1M146V), and tau P301L mutant (htauP301L) transgene. Our results indicate significant region-specific alterations in myelination patterns and in oligodendrocyte marker expression profiles in the 3xTg-AD mice at time points preceding the appearance of amyloid and tau pathology. These immunohistochemical signatures coincide with age-related alterations in axonal and myelin sheath ultrastructures as visualized by comparative electron microscopic examination of 3xTg-AD and non-transgenic (NonTg) mouse brain tissue.;The 3xTg-AD mice exhibit significant intracellular Abeta1--42 and oligomeric Abeta accumulation at stages corresponding to white matter abnormalities. We next investigated the possible involvement of amyloid beta 1--42 (Abeta1--42) in oligodendrocyte and myelin disruption in vivo. To this end, we constructed a recombinant adeno-associated virus serotype-2 (rAAV2) vector expressing Abeta1--42 specific intracellular antibody (intrabody) or phenobarbitol control intrabody with an endoplasmic reticulum (ER) targeting signal. These vectors were stereotactically delivered to the hippocampi of 2 month-old 3xTg-AD mice and NonTg mice using convection-enhanced delivery (CED). Four months of chronic expression of the Abeta1--42 specific, ER-targeted intrabody led to protection of oligodendrocyte and myelin homeostasis in the brains of treated 3xTg-AD mice.;While 3xTg-AD mice harbor hAPPswe and tauP301L transgenes that are exclusively expressed in neurons, the hPS1 M146V knock-in mutation is expressed in neurons and glia, including oligodendrocytes. Oligodendrocytes harboring hPS1M146V have demonstrated increased sensitivity to Abeta-induced glutamate toxicity in previous studies, thus implicating hPS1M146V in Abeta 1--42 induced alterations in oligodendrocyte function in the 3xTg-AD mice. To further explore this phenomenon and potentially identify pathogenic effects that recapitulate what we observed in the setting of 3xTgAD mice, we utilized an in vitro system where mouse oligodendrocyte precursor (mOP) cells were transiently transfected to express hPS1 WT and hPS1M146V proteins. Flow cytometry analyses indicated that hPS1M146V expression combined with Abeta 1--42 exposure specifically increased the number of CCl-positive cells, while myelin basic protein (MBP)-positive cell numbers remained unchanged. Although overall MBP protein levels were unaffected, hPS1M146V expression exacerbated Abeta1--42 induced disruption of MBP subcellular distribution and myelination activity in differentiating mOP cells. Most notably, inhibition of GSK-3beta activity in hPS1M146V -transfected/Abeta1--42-treated differentiating mOP cells led to significant correction of MBP subcellular distribution and in vitro myelination defects.;These findings provide valuable insights into the molecular mechanisms underlying Abeta1--42 effects on the temporal and spatial progression of white matter disruption in the early pre-symptomatic stages of AD pathology and may illuminate new therapeutic strategies designed to avert these early impairments.