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Prion-like seeding and propagation of Tau-pathology have been demonstrated experimentally and may underlie the stereotyped progression of neurodegenerative Tauopathies. However, the involvement of templated misfolding of Tau in neuronal network dysfunction and behavioral outcomes remains to be explored in detail. Here we analyzed the repercussions of prion-like spreading of Tau-pathology via neuronal connections on neuronal network function in TauP301S transgenic mice. Spontaneous and GABAR-antagonist-induced neuronal network activity were affected following templated Tau-misfolding using synthetic preformed Tau fibrils in cultured primary neurons. Electrophysiological analysis in organotypic hippocampal slices of Tau transgenic mice demonstrated impaired synaptic transmission and impaired long-term potentiation following Tau-seed induced Tau-aggregation. Intracerebral injection of Tau-seeds in TauP301S mice, caused prion-like spreading of Tau-pathology through functionally connected neuroanatomical pathways. Electrophysiological analysis revealed impaired synaptic plasticity in hippocampal CA1 region 6 months after Tau-seeding in entorhinal cortex (EC). Furthermore, templated Tau aggregation impaired cognitive function, measured in the object recognition test 6 months post-seeding. In contrast, Tau-seeding in basal ganglia and subsequent spreading through functionally connected neuronal networks involved in motor control, resulted in motoric deficits reflected in clasping and impaired inverted grid hanging, not significantly affected following Tau-seeding in EC. Immunostaining, biochemical and electron microscopic analysis in the different models suggested early pathological forms of Tau, including Tau-oligomers, rather than fully mature neurofibrillary tangles (NFTs) as culprits of neuronal dysfunction. We here demonstrate for the first time using in vitro, ex vivo and in vivo models, that prion-like spreading of Tau-misfolding by Tau seeds, along unique neuronal connections, causes neuronal network dysfunction and associated behavioral dysfunction. Our data highlight the potential relevance of this mechanism in the symptomatic progression in Tauopathies. We furthermore demonstrate that the initial site of Tau-seeding thereby determines the behavioral outcome, potentially underlying the observed heterogeneity in (familial) Tauopathies, including in TauP301 mutants. [ABSTRACT FROM AUTHOR]

Our institution is currently engaged in ongoing genetic studies of familial Alzheimer's disease (AD), which include clinical ascertainment and brain autopsy of both affected and non-affected family members. Here we describe the analysis of 22 AD families, each with at least one family member with a postmortem diagnosis of dementia with Lewy bodies (DLB). For this study, 47 brains were examined according to NINCDS-Reagan Institute criteria for the diagnosis of AD. Lewy body pathology was evaluated with α-synuclein immunohistochemistry. Four families, with either one or two autopsies showing Lewy body pathology, demonstrated linkage to 12p. Five families had two or more autopsies with Lewy body pathology, but their linkage status was unknown. The remaining 13 families had one autopsy demonstrating Lewy bodies. These findings suggest that at least one pathological form of DLB may be familial. In some families, the pathological phenotype is identical in all examined affected family members; but in others, there may be several pathologies that coexist. Careful neuropathological examination of affected family members may prove critical for future genetic analysis of AD and DLB. [ABSTRACT FROM AUTHOR]

To investigate similarities and differences between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), we undertook a demographic analysis of 277 patients from the Kathleen Price Bryan Brain Bank with an antemortem diagnosis of probable AD. Patients with additional, possibly confounding clinical and pathologic diagnoses such as infarcts, hematomas, neoplasms, and other neurodegenerative disorders, were excluded from the analysis. Neuropathologically, AD alone was present in 192 subjects (69%), and DLB was found in 85 subjects (31%). All of the DLB cases had neuropathologic evidence of AD sufficient to meet CERAD criteria for a diagnosis of definite AD plus nigral Lewy bodies. Gender, apolipoprotein E (APOE) genotype, brain weight, age at death, duration of disease and Braak stage were compared between the two groups. Statistical analyses were performed using Fisher's exact test for comparisons of categorical data and Student's t-test for comparison of means for continuous outcomes. The proportion of males and females was balanced in the combined AD and DLB populations. There was a highly statistically significant increased frequency of APOE 3/4 in males with DLB (P=0.007). We found higher brain weights in males with DLB versus males with AD (P=0.012). AD was more frequent in females and DLB was more frequent in males (P=0.019). Our findings with respect to age at death, duration of disease and Braak stage within diagnostic groups confirm previously reported findings. These data suggest that Lewy bodies are more common in males affected with dementia, especially those with the APOE 3/4 genotype. [ABSTRACT FROM AUTHOR]

Mutations in the amyloid precursor protein (APP) gene cause one form of early onset familial Alzheimer’s disease (AD). One such family has been studied genetically and neuropathologically and represents the basis of the present report. Four siblings with the APP717 Val to Ile mutation, aged 59, 65, 61 and 64 years, apolipoprotein E (APOE) genotyped 2,4 (first three) and 2,3 respectively, had severe AD, Braak stage VI with frequent neurofibrillary tangles in the primary visual cortex, Brodmann area 17. The first one also met McKeith criteria for the limbic stage of dementia with Lewy bodies but did not have substantia nigra Lewy bodies. The second two met McKeith criteria for the neocortical stage of dementia with Lewy bodies and both had substantia nigra Lewy bodies. The fourth had AD but no Lewy bodies. A cousin without the APP717 mutation who was APOE 3, 4, developed dementia at age 60 and died at age 75. She had severe cerebrovascular atherosclerosis, less severe AD, Braak stage V, with sparing of area 17. She also had Lewy bodies in the substantia nigra and in the cortex and met McKeith criteria for neocortical stage of dementia with Lewy bodies. Extrapyramidal features were present in all five. Lewy bodies have been described in 53% of reported autopsies on individuals with the APP717 Val to Ile mutation coincident with dementia and AD neuropathologic changes. These observations suggest an association between the chromosome 21 APP mutation and Lewy body formation, possibly mediated by other environmental or genetic factors. [ABSTRACT FROM AUTHOR]

In a retrospective cliniconeuropathological study, we reviewed all the cases received in our dementia brain bank during a 4-year period to determine if all patients with severe substantia nigra (SN) degeneration and SN Lewy bodies (LBs) exhibited prominent signs of parkinsonism and were treated for parkinsonism during the disease course. The SN of 426 cases were graded for microscopic degeneration using a semiquantitative five-tiered scale, with grade 0 indicating normal and grade 4 the most severe degeneration. Twenty-nine cases with grade 3 (16) or grade 4 (13) SN degeneration with SN LBs and clinical records were identified. Ten had been treated for parkinsonism (6 grade 3, 4 grade 4) and 19 had not. Whereas most of the patients had exhibited signs of end-stage parkinsonism during their last year, 1 grade 3 and 2 grade 4 patients apparently never exhibited prominent signs of parkinsonism during the course of their dementia. No clear neuropathological differences were noted between these patients that did not have prominent signs and a control group of six patients with clinical Parkinson’s disease with dementia (parkinsonism onset at least 1 year before dementia onset). We conclude that in patients with dementia there is an inconsistent relationship between the expression of clinical parkinsonism during life and severe SN degeneration with LBs identified at necropsy. [ABSTRACT FROM AUTHOR]