Lipoproteins and Related Molecules in Alzheimer’s Disease CHI PUI PANG* AND LARRY BAUM Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China INTRODUCTION Alzheimer’s disease (AD) is a neuro-degenerative disease of the central nervous system characterized by progressive memory loss and other cognitive de- terioration. AD pathology is involved with formation of neurofibrillary tangles and neuritic plaques in the brain. Its occurrence is pan-ethnic, affecting as many as 5 to 10% of people aged more than 65 years. The incidence almost doubles every 5 years for people between 65 and 80 years old in the Caucasian popu- lation (Katzman and Kawas, 1994). So far there is no cure for the disease, and the eventual clinical and prognostic outcomes are grievous. While more than 10 genetic loci have evident or putative associations with AD, a spectrum of secondary factors including age, gender, family history, head injury, and insulin resistance have been implicated risk factors. The etiology of AD is clearly multi-factorial, involving a multitude of genetic and environmental factors (Far- rer and Cupples, 1994). GENETICS OF ALZHEIMER’S DISEASE Two dominant risk factors of AD are advanced age and family history (Finch and Cohen, 1997). Linkage and association studies have revealed susceptibility genes for AD, especially the early-onset cases. Muta- tions in three genes, -amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) in chromosomes 14, 1, and 21, respectively, can cause early-onset AD. ApoE ε4 is responsible for a large por- tion of late-onset AD cases. Polymorphisms in the APOE promoter may affect levels of apoE and AD risk (Bullido and Valdivieso, pages 261–267, this issue). Polymorphisms in other genes, including alpha 2 -mac- roglobulin (A2M), low density lipoprotein receptor-re- lated protein (LRP), and perhaps lipoprotein lipase (LPL), also affect late-onset AD risk. These late-onset risk factor genes all play roles in lipoprotein transport, with apoE and A2M transporting lipids and other mol- ecules to one of their major receptors in the brain, LRP, with the interaction mediated by LPL. Links between these proteins and the early onset AD genes are being revealed (Van Uden et al., pages 268 –272, this issue). Polymorphisms in receptors related to LRP, such as very low density lipoprotein receptor (VLDLR), have also been studied, but without revealing consistent as- sociation with AD (Helbecque and Amouyel, pages 273–277, this issue). POSSIBLE ROLE OF LIPOPROTEINS AND RELATED MOLECULES The apolipoprotein E (apoE) ε4 allele increases risk of Alzheimer’s disease (AD), perhaps by acceler- ating plaque formation, or by impairing neuron re- pair (Baum et al., pages 278 –281, this issue). ApoE4 inhibits amyloid  protein (A) aggregation less ef- fectively than apoE3, and the ε4 allele is associated with more amyloid deposits, supporting an effect of apoE on A aggregation. ApoE ε4 worsens neurolog- ical impairment in AD, in other brain insults, and in aged mice, supporting an effect of apoE on neurite maintenance. Therefore, apoE may play a role in AD by both mechanisms. In AD brain, evidence suggests that lipoproteins in the cerebrospinal fluid (CSF) have suffered increased free radical damage (Bassett et al., pages 282–286, this issue). Since oxidized human CSF lipoproteins are toxic to cultured neurons, CSF lipoproteins may contribute to the neuronal damage in AD. Dietary cholesterol increases accumulation of A in the brain, and heart disease is associated with Alzhei- mer’s disease (Sparks et al., pages 287–290, this issue). Thus, lipoproteins may affect AD risk via their role in cholesterol transport, and reduction of cholesterol levels might be a treatment for AD. Meanwhile, the earliest and most extensive lesions in AD brains are usually found in the hippocampus. LPL is relatively concentrated in hippocampus than other brain regions, and is found in AD amyloid plaques. It might, therefore, affect hippocampal function and thus dementia via its role as supplier of membrane components or antioxidants to neurons (Baum et al., pages 291–296, this issue). ApoE is produced by astrocytes and is abundant in CSF in lipoproteins the size of large plasma high-den- sity lipoproteins (HDL). Different isoforms of apoE have different effects on neurite outgrowth, neuronal plasticity, neurotoxicity, oxidative injury, interactions with A, and neuritic plaque formation (Fagan and Holtzman, pages 297–304, this issue). Apolipoprotein J (clusterin) is a widespread, multifunctional protein that can bind many molecules (Calero et al., pages 305–315, this issue). It is a transporter of molecules, including A, across the blood-brain barrier. Like ApoE, ApoJ is present in amyloid plaques. The fact that both molecules are up-regulated after neuronal injury suggests they protect neurons from stress, per- haps in part by acting as extracellular chaperones, binding to hydrophobic regions of partially unfolded, stressed proteins, and, therefore, avoiding aggregation. Interaction between these apolipoproteins and A might be explained by this role. Despite the large amount of research on A, its clearance has received much less attention than its production, until recently. *Correspondence to: Professor C.P. Pang, Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, 147K Argyle Street, Kowloon, Hong Kong. E-mail: cppang@cuhk.edu.hk Received 15 March 2000; accepted in revised form 6 April 2000 MICROSCOPY RESEARCH AND TECHNIQUE 50:259 –260 (2000) © 2000 WILEY-LISS, INC.