Homing in on Intracellular Aβ?

mers or ADDLs appear to accumulate in the AD brain. These soluble aggregates have been shown to be potent neurotoxins that can acutely disrupt neuronal func-In this issue of Neuron, a study by Billings et al. tion in vivo. The limited immunohistochemical studies points to intracellular A␤ as a possible cause of neu-using antibodies that recognize these oligomers or ronal dysfunction. In a mouse model of Alzheimer's ADDLs suggest that these forms of Aβ bear no spatial disease, Billings et al. link appearance of intraneuro-relationship to either compact or diffuse plaques nal A␤ to cognitive impairments and then show that (Kayed et al., 2003; Klein et al., 2004). " clearance " of intraneuronal A␤ by anti-A␤ antibodies One of the values of studying learning and memory restores cognitive deficits. in animal models of human neurodegenerative diseases is the ability to potentially relate cognitive and physio-logic alterations to the pathological alterations in the brain. Such studies may ultimately provide a better un-Alzheimer's disease (AD) is characterized by a pro-derstanding of the factors that lead to cognitive dys-gressive decline in cognitive abilities. Especially pro-function in mice, reveal novel therapeutic targets, and found are the deficits in learning and memory. Ana-enable preclinical testing of therapeutic strategies tomic and pathologic correlates of these functional through cognitive endpoints. In this respect, the manu-deficits are apparent in the postmortem human AD script by Billings and colleagues (2005 [this issue of brain. Neuronal dystrophy and death are observed in Neuron]), which provides a detailed cognitive charac-brain regions critical for these functions, as are the terization of the 3xTg-AD mouse model of AD, is a valu-other pathological hallmarks of AD, namely senile able contribution to the AD field. This model expresses plaques, neurofibrillary tangles, and gliosis. The rela-both the AD-linked mutant APPNL and FTDP-17-linked tionship between pathological abnormalities and cog-mutant tau P301L transgenes in a presenilin-1 mutant nitive deficits in early stages of Alzheimer's disease knockin background. A series of lucid and well-designed (e.g., mild cognitive impairment [MCI]) is less well behavioral experiments that separate the effects of the established. However, studies of glucose metabolism transgene(s) from possible nonspecific effects on other in the brains of APOE4 carriers at risk for AD (Small behavioral systems are reported. et al., 1995), longitudinal volumetric brain imaging of The authors evaluate the 3xTg-AD mice using a hip-individuals with presenilin mutations as they convert to pocampal-dependent reference memory version of the AD …