**1. Introduction**

Alzheimer's disease (AD), the most common cause of dementia, was discovered by Alois Alzheimer in 1901. The prevalence of AD is about 1% in individuals aged 60–64, but shows an exponential increase with age, so that in people aged 85 years or older the prevalence is between 24–33% in the Western World. The hallmarks of the disease are extracellular deposits of plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles, composed of hyperphosphorylated tau (phospho-tau), a normal axonal protein that binds to microtubules [1]. The relationship among Aβ deposits, tangle formation and neurodegeneration, and cell death is not clear at present. The areas more vulnerable for the neurodegeneration processes are the cortex and the hippocampus, affecting mechanisms of spatial, semantic and episodic memories [2]. Other processes implicated in the pathological pathways in AD are cholinergic dysfunction, neuroinflammation, calcium channels, oxidation, iron chelation, abnormalities in the mitochondrial DNA and lipid metabolism, among others [3].

Therapeutic strategies in AD trying to ameliorate or eliminate its main disturbances, include the elimination of Aβ deposits, vaccination and immunization against Aβ, inhibitors of β or γ-secretases (enzymes excising Aβ from APP), antifibrillisation agents, statins (inhibitors of cholesterol synthesis), neuroprotectors, antioxidants and anti-inflammatory drugs, among others (reviewed in [4]). However, although the pathological hallmarks of AD are well defined, no effective therapy exists currently.

Liver growth factor (LGF) is a hepatic mitogen purified in 1986 by Dr. Diaz-Gil's group [5]. This 64 kDa factor is an albumin–bilirubin complex that stimulates the proliferation of different cell types, and promotes regeneration of damaged tissues including the brain (reviewed in [6]). Thus, administration of LGF was able to stimulate axonal growth in the striatum, to increase the number of dopaminergic neurons in the damaged substantia nigra, and to improve rotational behavior stimulated by apomorphine in experimental Parkinson's disease [7,8]. LGF also promoted the proliferation and migration of neural progenitors from the forebrain subventricular zone [9], and improved the viability, differentiation and integration of stem cell grafts into the host tissue [10]. Besides, our previous studies have reported the remarkable anti-inflammatory and antioxidant activities of LGF in extracerebral tissues [11–13], and in several experimental models of neurodegeneration where its main cellular target in the brain appears to be microglia [7,9,14,15]. Both effects are considered to be closely related with Alzheimer's disease pathology [16,17].

To analyze the potential therapeutic effectiveness of LGF in AD, we have used Tg2576 transgenic mice (from now APPswe mice) that over-express the Swedish APP mutation (K670N/M671L) on a C57Bl/6 9 SJL background [18]. From 12 months onwards, these mice show Aβ plaque depositions in the hippocampus and cerebral cortex, reactive gliosis, inflammation and cognitive impairment that are neuropathological features of AD [19]. Chronic LGF administration to a 20–21-month-old APPswe mouse, significantly reduces Aβ and phospho-Tau protein levels and modulates protein ubiquitination and the expression of the heat shock protein 70 (Hsp70) that is involved in Aβ clearance. LGF also reduces microglia activation, astrogliosis and the expression of the apoptosis-associated speck-like protein containing a CARD (ASC), which is a component of the inflammatory response and cognitive impairment in AD pathology. Moreover, LGF up-regulates the expression of the Nuclear factor erythroid 2-related factor 2 (Nrf2), which plays an important role against oxidative stress. Because these beneficial effects correlate with a better cognitive outcome in APPswe mice, we may propose LGF as a potential novel therapeutic tool that may be useful for the treatment of AD.
