Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease 1. In the disease process neuronal tau inclusions first appear in transentorhinal cortex, from where they appear to spread to hippocampal formation and neocortex 2. Cognitive impairment becomes manifest when inclusions reach the hippocampus, with abundant neocortical tau inclusions and extracellular β-amyloid deposits being the defining pathological hallmarks of Alzheimer's disease. Abundant tau inclusions, in the absence of β-amyloid deposits, define Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases 1. Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia 3-5. Thus, transgenic mice expressing mutant (e.g. P301S) human tau in nerve cells exhibit the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein 6,7. In contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or display neurodegeneration 7,8. Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that the injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces the assembly of wild-type human tau into filaments and the spreading of pathology from the site of injection to neighbouring brain regions.

Mutations in the amyloid precursor protein (APP) gene cause early-onset familial Alzheimer disease (AD) by affecting the formation of the amyloid ␤ (A␤) peptide, the major constituent of AD plaques. We expressed human APP 751 containing these mutations in the brains of transgenic mice. Two transgenic mouse lines develop pathological features reminiscent of AD. The degree of pathology depends on expression levels and specific mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670͞671 combined with the V717I mutation causes A␤ deposition in neocortex and hippocampus of 18-month-old transgenic mice. The deposits are mostly of the diffuse type; however, some congophilic plaques can be detected. In mice with 7-fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appear at 6 months, which increase with age and are Congo Red-positive at first detection. These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inf lammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology. The immunoreactivity is exclusively found in congophilic senile plaques of both lines. In the higher expressing line, elevated tau phosphorylation can be demonstrated biochemically in 6-month-old animals and increases with age. These mice resemble major features of AD pathology and suggest a central role of A␤ in the pathogenesis of the disease.

Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer's disease, tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer's disease and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. We previously demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. Here we injected brain extracts from humans who had died with various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice. Argyrophilic tau inclusions formed in all cases and following the injection of the corresponding brain extracts, we recapitulated the hallmark lesions of AGD, PSP and CBD. Similar inclusions also formed after intracerebral injection of brain homogenates from human tauopathies into nontransgenic mice. Moreover, the induced formation of tau aggregates could be propagated between mouse brains. These findings suggest that once tau aggregates have formed in discrete brain areas, they become self-propagating and spread in a prion-like manner.

Mutations in the ␣-synuclein (␣SYN) gene are associated with rare cases of familial Parkinson's disease, and ␣SYN is a major component of Lewy bodies and Lewy neurites. Here we have investigated the localization of wild-type and mutant [A30P]␣SYN as well as ␤SYN at the cellular and subcellular level. Our direct comparative study demonstrates extensive synaptic colocalization of ␣SYN and ␤SYN in human and mouse brain. In a sucrose gradient equilibrium centrifugation assay, a portion of ␤SYN floated into lower density fractions, which also contained the synaptic vesicle marker synaptophysin. Likewise, wild-type and [A30P]␣SYN were found in floating fractions. Subcellular fractionation of mouse brain revealed that both ␣SYN and ␤SYN were present in synaptosomes. In contrast to synaptophysin, ␤SYN and ␣SYN were recovered from the soluble fraction upon lysis of the synaptosomes. (Surguchov et al., 1999). The central domain of ␣SYN had been originally identified as the non-amyloid ␤-protein component (NAC) of Alzheimer's disease plaques (Uéda et al., 1993). Full-length ␣SYN has been subsequently found in Lewy bodies (LBs), pale bodies, and Lewy neurites of patients with Parkinson's disease (PD) and dementia with LBs, as well as in cytoplasmic inclusions characteristic for multiple system atrophy (Spillantini et al., 1997;Arima et al., 1998;Baba et al., 1998;Spillantini et al., 1998;Takeda et al., 1998a;Tu et al., 1998;Wakabayashi et al., 1998;Culvenor et al., 1999). LBs were ␣SYN-positive in LB variant of Alzheimer's disease, familial Alzheimer's disease, and Down's syndrome (Lippa et al., 1998(Lippa et al., , 1999Takeda et al., 1998b), as well as in neurodegeneration with brain iron accumulation type 1 (formerly known as HallervordenSpatz disease) (Arawaka et al., 1998;Wakabayashi et al., 1999).Two missense mutations in the ␣SYN gene have been linked to familial PD (Polymeropoulos et al., 1997;Krüger et al., 1998). Both mutations accelerated the intrinsic property of ␣SYN to selfaggregate into fibrils that were morphologically similar to those isolated from LBs (Conway et al., 1998;Giasson et al., 1999;Narhi et al., 1999). Therefore, similar to most of the mutations associated with other familial forms of neurodegenerative disorders, ␣SYN mutations lead to the abnormal generation of an amyloidogenic variant, which is deposited in the disease-specific lesion (Hardy and Gwinn-Hardy, 1998;Lansbury, 1999;Selkoe, 1999).The physiological function of synucleins is unknown. Targeted disruption of the ␣SYN gene in mice caused a subtle perturbation in dopaminergic neurotransmission (Abeliovich et al., 2000). The identification of ␣SYN binding proteins has pointed to potential roles in signal transduction, perhaps in the context of axonal transport (Jenco et al., 1998;Engelender et al., 1999;Jensen et al., 1999;Ostrerova et al., 1999). Another link to signal transduction events may be indicated by the fact that both ␣SYN and ␤SYN are phosphorylated Okochi et al., 2000).Previous immunohistochemical studies suggested an enrichme...