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Am J Neurodegener Dis 2013;2(3):187-207

Original Article
Subjects harboring presenilin familial Alzheimer’s disease mutations
exhibit diverse white matter biochemistry alterations

Alex E Roher, Chera L Maarouf, Michael Malek-Ahmadi, Jeffrey Wilson, Tyler A Kokjohn, Ian D Daugs, Charisse M
Whiteside, Walter M Kalback, MiMi P Macias, Sandra A Jacobson, Marwan N Sabbagh, Bernardino Ghetti, Thomas G

The Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health Research Institute, Sun City, AZ 85351;
Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute, Sun City, AZ 85351; Department of
Economics, W. P. Carey School of Business, Arizona State University, Tempe, AZ 85287; Department of Microbiology,
Midwestern University School of Medicine, Glendale, AZ 85308; University of Arizona College of Medicine, Phoenix, AZ
85004; Indiana Alzheimer Disease Center and Department of Pathology and Laboratory Medicine, Indiana University
School of Medicine, Indianapolis, IN 46202; Civin Laboratory for Neuropathology, Banner Sun Health Research
Institute, Sun City, AZ 85351

Received August 2, 2013; Accepted August 30, 2013; Epub September 18, 2013; Published September 30, 2013

Abstract: Alzheimer’s disease (AD) dementia impacts all facets of higher order cognitive function and is characterized
by the presence of distinctive pathological lesions in the gray matter (GM). The profound alterations in GM structure and
function have fostered the view that AD impacts are primarily a consequence of GM damage. However, the white matter
(WM) represents about 50% of the cerebrum and this area of the brain is substantially atrophied and profoundly
abnormal in both sporadic AD (SAD) and familial AD (FAD). We examined the WM biochemistry by ELISA and Western
blot analyses of key proteins in 10 FAD cases harboring mutations in the presenilin genes PSEN1 and PSEN2 as well
as in 4 non-demented control (NDC) individuals and 4 subjects with SAD. The molecules examined were direct
substrates of PSEN1 such as Notch-1 and amyloid precursor protein (APP). In addition, apolipoproteins, axonal
transport molecules, cytoskeletal and structural proteins, neurotrophic factors and synaptic proteins were examined.
PSEN-FAD subjects had, on average, higher amounts of WM amyloid-beta (Aβ) peptides compared to SAD, which may
play a role in the devastating dysfunction of the brain. However, the PSEN-FAD mutations we examined did not produce
uniform increases in the relative proportions of Aβ42 and exhibited substantial variability in total Aβ levels. These
observations suggest that neurodegeneration and dementia do not depend solely on enhanced Aβ42 levels. Our data
revealed additional complexities in PSEN-FAD individuals. Some direct substrates of γ-secretase, such as Notch, N-
cadherin, Erb-B4 and APP, deviated substantially from the NDC group baseline for some, but not all, mutation types.
Proteins that were not direct γ-secretase substrates, but play key structural and functional roles in the WM, likewise
exhibited varied concentrations in the distinct PSEN mutation backgrounds. Detailing the diverse biochemical
pathology spectrum of PSEN mutations may offer valuable insights into dementia progression and the design of
effective therapeutic interventions for both SAD and FAD. (AJND1308001).

Keywords: Sporadic Alzheimer’s disease, familial Alzheimer’s disease, presenilin, γ-secretase, white matter, gray
matter, amyloid precursor protein, amyloid-beta

Address correspondence to: Dr. Alex E Roher, Longtine Center for Neurodegenerative Biochemistry, Banner Sun
Health Research Institute, 10515 W. Santa Fe Dr., Sun City AZ, 85351. Tel: (623)-832-5465; Fax: 623-832-5698; E-mail: