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Molecular Problem

Alzheimer’s disease (AD), the most prevalent dementing disorder, occurs in an estimated 5.7% to 10% of the United States population 65 to 85 years of age and 25% to 45% of those 85 years of age or older (U.S. General Accounting Office, 1998).

AD is characterized by loss of nerve cell membrane communication centers (synapses) leading to neuronal cell death accompanied by the formation of end-stage protein deposits (senile plaques and neurofibrillary tangles) in the brain.

The initial molecular events in AD that culminate in neuronal cell death are thought to relate to abnormal membrane repair mechanisms and probably start decades before the onset of symptoms (first proposed by Dr. Pettegrew during an address to the United States Senate Special Committee Meeting on Aging, Overview of the Molecular Biology of Alzheimer’s Disease and the Outlook for Treatment and Prevention, Washington, DC, January 22, 1991).

Research studies of AD autopsy brain tissue and in vivo magnetic resonance spectroscopy (MRS) brain studies of AD subjects reveal distinct alterations in brain membrane phospholipid metabolism (Pettegrew et al., 1984; 1988a; 1994; 1995; 2000; 2002; 2005; Klunk et al., 1995; 1996), composition (Pettegrew et al., 2001) and select enzyme activity (Kanfer et al., 1993). These alterations correlate with both neuropathological findings of senile plaques and neurofibrillary tangles and with clinical measures of cognitive decline (Pettegrew et al., 1988b).  In one individual, the molecular changes occurred 5 years prior to any minimal cognitive alterations (Pettegrew et al., 1995).  In addition, in vivo MRS brain studies of AD subjects reveal findings of energetic stress (Pettegrew et al., 1994) and loss of synaptic/transport vesicles  (Pettegrew et al., 2002).

A prominent membrane phospholipid breakdown product (glycerophosphocholine, GPC), whose brain levels go up with normal aging (Pettegrew et al., 1990) and 2-3 fold further in AD brain (Klunk et al., 1996), has been shown to enhance the aggregation of Ab(1-40) 3-4 fold (Klunk et al., 1997).  Further studies reveal that GPC binds to Ab(1-40) and enhances a b-turn (McClure et al., 2001) in the α-helical Ab(1-40) which would enhance b-sheet formation and aggregation (Mandal et al., 2004).  Recently it has been shown that Ab(1-40) in a hydrophilic environment (PBS, pH 7.4) induces the slow catalytic cleavage of GPC to phosphocholine (PC) + glycerol (Pettegrew et al., 2005).  This catalytic cleavage in vivo would lead to reduced cellular choline levels resulting in reduced acetylcholine synthesis; cholinergic deficits are well documented in AD.  Ab(1-40) and GPC are both produced by normal membrane constituents (amyloid precursor protein ® Ab(1-40) and phosphatidylcholine ® GPC) and both Ab(1-40) and GPC insert into the phospholipid head group region of normal membranes (Mandal et al., 2004).  In normal membranes, Ab(1-40) does not induce the catalytic breakdown of GPC.  In model membranes with loosened phospholipid packing, Ab(1-40) induces catalytic cleavage of GPC to PC + glycerol and choline + α-glycerophosphate.  In summary, membrane abnormalities have been shown to underlie and probably initiate many of the known neuropathological and clinical findings in AD.