Neurotox Res (2009) 16:306–317 a high ratio of mRNA encoding mutated hAPP versus wt mouse APP (Rockenstein et al. 1995) that promotes development of typical amyloid plaques, dystrophic neu- rites, loss of presynaptic terminals, astrocytosis, and microgliosis (Games et al. 1995; Masliah et al. 1996b; Games et al. 1997). Other models have expressed mutant hAPP under the regulatory control of either the human or murine (m)Thy-1 promoter (Andra et al. 1996; Sturchler-Pierrat et al. 1997; Moechars et al. 1999; Bornemann and Staufenbiel 2000) or the protease-resistant prion protein (PrP) promoter (Hsiao et al. 1996; Borchelt et al. 1997). Amyloid deposition begins at 12 months of age; however, co-expression of mutant PS1 accelerates amyloid deposition, beginning at 4 months of age (Borchelt et al. 1996; Borchelt et al. 1997; Holcomb et al. 1998). Another more recently developed model, where APP is also expressed under the control of the PrP promoter, displays even earlier onset of amyloid deposition, starting at 3 months and progressing to mature plaques and neuritic pathology from 5 months of age, accompanied by high levels of Ab1–42 (Chishti et al. 2001). While the PrP promoter has provided several models that mimic aspects of familial AD (FAD), other promoters targeting expression of APP to neurons provide alternative models demonstrating pathology that recapitulate similar and additional aspects of FAD. In this regard, we have generated lines of tg mice expressing hAPP751 cDNA containing the London (V717I) and Swedish (K670M/ N671L) mutations under the regulatory control of the murine (m)Thy-1 gene (mThy1-hAPP751) (Rockenstein et al. 2001). Therefore, while expression of mutant hAPP under the PDGF-b promoter results in the production of diffuse (and some mature) plaques (Games et al. 1995; Mucke et al. 2000), tg expression of mutant hAPP under the mThy-1 (Andra et al. 1996) and PrP (Hsiao et al. 1996; Borchelt et al. 1997) promoters favors the formation of mature plaques in the hippocampus and neocortex. This suggests that the differential patterns of Ab deposition might be dependent on the speciﬁc neuronal populations selected by the promoter, levels of expression and topo- graphical distribution of the transgene, and levels of Ab1–40 and Ab1–42. Consistent with this, in FAD and Down syn- drome, production of high levels of Ab1–42 results in early plaque formation (Citron et al. 1997). This suggests that early age of onset and plaque formation depends on high levels of Ab1–42 production (Rockenstein et al. 2001). More recent models have been focused toward modeling the role of Ab protoﬁbril generation and other mutations in APP in the pathogenesis of AD. Of them, the most inter- esting are those expressing APP bearing the Arctic muta- tion. These mice rapidly develop extensive plaque formation (Cheng et al. 2004). For a review of these and additional tg models of neurodegenerative disease, please 309 visit the Alzheimer’s Forum website at: http://www.alz forum.org/res/com/tra. a-Synuclein Transgenic Models of PD and LBD Since progressive intraneuronal aggregation of a-syn has been proposed to play a central role in the pathogenesis of PD and related disorders (Hashimoto and Masliah 1999; Trojanowski and Lee 2000; Volles and Lansbury 2002), most tg models have been focused at investigating the in vivo effects of a-syn accumulation utilizing neuron-spe- ciﬁc promoters. Several recent reviews have been pub- lished addressing this subject (Hashimoto et al. 2003a; Fernagut and Chesselet 2004). Among these models, overexpression of wt a-syn under the regulatory control of the PDGF-b promoter has been shown to result in motor deﬁcits, dopaminergic loss, and formation of inclusion bodies (Masliah et al. 2000). Mice with the highest levels of expression (line D) showed intraneuronal accumulation of a-syn that started at 3 months of age and was accom- panied by the loss of tyrosine hydroxylase (TH) ﬁbers in the caudoputamen region and synapses in the temporal cortex. Although no apparent neuronal loss was detected in the substantia nigra (SN), measurements of dopamine levels in the caudoputamen region showed a 25–50% reduction at 12 months of age. Consistent with these results, tg mice showed mild to moderate motor deﬁcits in the rotarod, particularly in mice with the greatest loss of dopamine, indicating that more substantial deﬁcits ([75%) of this transmitter might be necessary for more overt def- icits to appear. In mThy-1-hasyn tg mice, this protein accumulated in synapses and neurons throughout the brain, including the thalamus, basal ganglia, SN, and brainstem (Rockenstein et al. 2002; Fleming et al. 2004). Because previous studies have shown that mutations associated with familial parkinsonism accelerate a-syn aggregation and oligomerization (Conway et al. 1998; Narhi et al. 1999), we compared the patterns of neurode- generation, a-syn aggregation, and neurological alterations in tg mice expressing wt or mutant (A53T) ha-syn at comparable levels under the PDGF-b promoter. Remark- ably, we found that mice expressing low levels of mutant ha-syn developed progressive motor deﬁcits and neurode- generation associated with ha-syn accumulation in syn- apses and neurons, but very few or no inclusions were found (Hashimoto et al. 2003a). Similarly, mice expressing high levels of mutant A53T, but not wt or A30P mutant, a-syn developed a severe and complex motor impairment leading to paralysis and death (Giasson et al. 2002; Lee et al. 2002; von Coelln et al. 2006). In contrast to our model expressing low levels of mutant a-syn, animals expressing higher levels of A53T a-syn developed age- dependent intracytoplasmic neuronal a-syn inclusions 123