Immunity and neuronal repair in the progression of Alzheimer’s disease: A brief overview Rona Baron a , Idan Harpaz b , Anna Nemirovsky a , Hagit Cohen b , Alon Monsonego a, * a Department of Microbiology and Immunology and the National Institute of Biotechnology in the Negev, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 84105, Israel b Ministry of Health, Mental Health Center, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University in the Negev, Beer-Sheva 84105, Israel Received 27 June 2006; accepted 5 July 2006 Available online 30 October 2006 Abstract Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disorder characterized by memory loss and severe cognitive decline. The etiology of the disease has not been explored, although a significant body of evidence suggests that neuronal dysfunction is caused by hyperphosphorylation and intracellular accumulation of the Tau protein, extracellular accumulation of the amyloid b-peptide (Ab), and the associated chronic activation of glial cells. Clearance of toxic Ab, apoptotic cells and debris from the brain together with induction of neuronal repair mechanisms may all take place partially throughout the progression of AD, but therapeutic approaches based on knowledge of these processes have been unsuccessfully developed. Here, we address the question of whether autoimmune mech- anisms can be boosted to safely facilitate the above-mentioned clearance and neuronal repair in the AD brain. We have previously dem- onstrated that depending on genetic background, autoimmunity targeted to Ab is already induced in elderly individuals and in patients with AD. We have shown in a mouse model of AD that given a preexisting proinflammatory milieu in the brain, immune cells can enter the brain tissue and participate in clearance of Ab. Furthermore, the decline in cognitive functions and neurogenesis throughout the pro- gression of AD may also be affected by autoimmune mechanisms operating in the periphery and in the brain. In light of the so-far unsuc- cessful anti-inflammatory approaches to treating AD, we suggest that boosting – rather than suppressing – the endogenous immune mechanisms induced in AD may enhance repair pathways in the brain, provided that this approach can be safely applied. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Alzheimer’s disease; Amyloid b-peptide; T-cell; Neurogenesis 1. Introduction The clinical features of Alzheimer’s disease (AD) are manifested morphologically by excessive accumulation in the brain parenchyma – particularly in the hippocampus and cerebral cortex – of extracellular amyloid b-peptide (Ab) in the form of amyloid plaques (Price and Sisodia, 1998; Selkoe, 2001). Although recent evidence suggests that soluble oligomers of Ab play a significant role in neuronal dysfunction (Walsh and Selkoe, 2004), aggregates of Ab that accumulate in the brain during aging become toxic in that they trigger chronic inflammation (Akiyama et al., 2000). Abnormal phosphorylation of the Tau protein and its accumulation as intracellular neuro-fibrillary tangles is also associated with apoptosis of neurons in AD (Alonso Adel et al., 2006; and Shahani et al., 2006). It is assumed that up to a certain threshold of this process the brain is able to compensate for these toxic effects and it may take as long as 10–15 yr for Ab to accumulate in the brain 0531-5565/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2006.07.001 Abbreviations: AD, Alzheimer’s disease; Ab, amyloid b-peptide; APP Tg, amyloid precursor protein in transgenic; IFN-c, interferon-gamma; BrdU, 5-bromo-2-deoxyuridine; DCX, doublecortin; IL-6, interleukin 6; Preg-S, pregnenolone sulfate; IGF-1, insulin-like growth factor; TNF-a, tumor necrosis factor-alpha; BBB, blood–brain-barrier; BDNF, brain- derived neurotrophic factor; bFGF, brain-derived neurotrophic factor; bFGF, basic fibroblast growth factor. * Corresponding author. Tel.: +972 8647 9052; fax: +972 8647 9051. E-mail address: alonmon@bgu.ac.il (A. Monsonego). www.elsevier.com/locate/expgero Experimental Gerontology 42 (2007) 64–69