Immunotherapy for Alzheimer’s Disease and Other Dementias Delphine Boche, James A.R. Nicoll, and Roy O. Weller Objective: The aim of this article is to review the role of immunotherapy in the removal of proteins which accumulate abnormally in neurodegenerative disorders associated with demen- tia, in particular amyloid-$ accumulation in Alzheimer’s disease. Results: In both transgenic mouse models and in two trials of amyloid-$ immunotherapy for human Alzheimer’s disease, active immunization with amyloid-$ 1Y42 results in the removal of amyloid-$ plaques from the cerebral cortex associated with, in the mouse models, improvement in cognitive function. Cerebral amyloid angiopathy and neurofibrillary tangles persist, however, and there is also concern about T lymphocyte immune reactions in the meninges in the human cases. Active immunization schedules are being developed to minimize T lymphocyte reactions and to maximize antibody production and passive immunization protocols are being devised. Immunotherapy for removal of the proteins which accumulate in other neurodegenerative disorders associated with dementia such as prion proteins and "-synuclein are in the early stages of development. Conclusion: Dementias in the elderly are an increasing medical, social and economic problem and current treatments are only effective. In the majority of dementias, proteins accumulate within cells and in the extracellular compartments of the brain. In the most common dementia, Alzheimer’s disease, amyloid-$ accumulates as plaques in the extracellular space of the grey matter and in artery walls as cerebral amyloid angiopathy and tau protein accumulates as neurofibrillary tangles within neurons. Key Words: Alzheimer’s disease, immunotherapy, neurodegenerative diseases, pathogenesis, prion Abbreviations: APP: amyloid precursor protein, CAA: cerebral amyloid angiopathy, ISF: interstitial fluid, NFT: neurofibrillary tangle, PrP: protease resistant protein (Clin Neuropharmacol 2006;29:22Y27) D ementia occurs mainly in those over the age of 65 years and shows a progressive increase with advancing age. Impairment of short and long-term memory, abstract think- ing, judgment, higher cortical function or personality change result in significant social and economic problems for patients and carers. There are a number of different causes of de- mentia and they are mainly defined by their pathological features (Table 1). Deposits of insoluble proteins or peptides occur within cells, either in the cytoplasm (e.g. tau, "- synuclein and ubiquitin) or in the nuclei as with huntingtin in Huntington’s disease; in the extracellular spaces of the brain and in blood vessel walls as cerebral amyloid angio- pathy (CAA) (e.g. amyloid-$). Other peptides accumulate in the brain parenchyma and blood vessel walls in familial dementias (e.g. the peptide deposited in the British type of dementia, ABri). 1 Vascular pathology also plays an impor- tant role in dementia both through cerebral infarction and possibly through impeding the elimination of proteins such as amyloid-$ from the brain. 2 White matter changes, detectable on imaging, are a feature especially in Alzheimer’s disease, cerebrovascular disease and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalo- pathy (CADASIL) 3 (Table 1) and may be due to ischaemia or to the failure of drainage of interstitial fluid. 4,5 ALZHEIMER’S DISEASE Alzheimer’s disease is the most common form of dementia and is characterized pathologically by the intra- cellular accumulation of tau in the form of neurofibrillary tangles (NFTs) in the cytoplasm of cortical neurons and the extracellular accumulation of amyloid-$ in grey matter (plaques) and in blood vessel walls (CAA). 6 NFTs are com- posed of hyperphosphorylated tau protein and ubiquitin and their accumulation may reflect a failure of the ubiquitin- proteosome system by which proteins within cells are eliminated. Amyloid-$ is derived from the transmembrane protein amyloid precursor protein (APP) through cleavage by a series of secretases. Two major forms of amyloid-$ are produced: the shorter more soluble form, amyloid-$ 1Y40, is 40 amino acids long and the longer, less soluble amyloid-$ 1Y42 contains 42 amino acids. Amyloid-$ 1Y40 accumulates mainly in blood vessel walls and amyloid-$ 1Y42 is a major component of plaques. The plaques of amyloid-$ are classi- fied as two main types: diffuse plaques are formed by insolu- ble amyloid-$ in the extracellular spaces deposited between neural processes and appear not to destroy surrounding brain tissue, whereas the compact or cored plaques disrupt brain REVIEW ARTICLE 22 Clin Neuropharmacol & Volume 29, Number 1, January - February 2006 From the Division of Clinical Neurosciences, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, SO16 6YD, UK. Reprints: Delphine Boche, Division of Clinical Neurosciences, University of Southampton, Mailpoint 813, South Pathology Block, Southampton General Hospital, Southampton SO16 6YD, UK (e-mail: D.Boche@ soton.ac.uk). This article was originally published in Current Opinion in Neurology. It is reprinted here as a service to our readers. Delphine Bolche, James A.R. Nicoll and Roy O. Weller. Immunotheraphy for Alzheimer’s disease and other dementias. Curr Opin Neurol 2005;118:720 Y725. Copyright * 2006 by Lippincott Williams & Wilkins Copyr ight © Lippincott Williams & Wilkins. Unauthor iz ed reproduction of this article is prohibited.