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.
Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease. In the disease process, neuronal tau inclusions first ...appear in the transentorhinal cortex from where they seem to spread to the hippocampal formation and neocortex. 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. An abundance of tau inclusions, in the absence of β-amyloid deposits, defines Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases. Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia. Thus, transgenic mice expressing mutant (for example, P301S) human tau in nerve cells show the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein. By contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or show neurodegeneration. Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces assembly of wild-type human tau into filaments and spreading of pathology from the site of injection to neighbouring brain regions.
Abstract The stereotypical pattern of neurofibrillary tangle spreading in the earliest stages of typical Alzheimer's dementia (AD) predicts that medial perirhinal cortex (mPRC) atrophy precedes ...entorhinal cortex (ERC) atrophy, whereas the status of the parahippocampal cortex (PHC) remains unclear. Atrophy studies have focused on more advanced rather than early AD patients, and usually segment the entire PRC as opposed to the mPRC versus lateral PRC (lPRC). The present study therefore determined the extent of ERC, mPRC, lPRC, and PHC atrophy in very early AD (mean Mini-Mental State Examination score = 26) patients and its presumed prodrome amnestic mild cognitive impairment (mean Mini-Mental State Examination score = 28) compared to demographically matched controls. PHG structures were manually segmented (blinded rater) and cortical thicknesses extracted. ERC and mPRC were similarly atrophied in both patient groups. The lPRC was atrophied in the AD group only. Thus, atrophic changes in very early AD broadly map onto the pattern of neurofibrillary tangle spreading and suggest that mPRC, ERC, and lPRC, but not PHC-associated functional impairments, characterize very early-stage AD.
Abstract Brain imaging measures of entorhinal cortex and hippocampus volumes provide valid and reliable markers of Alzheimer's disease (AD). Since AD neurofibrillary pathology begins more laterally ...in the transentorhinal region (TR) of the perirhinal cortex, volumetric measures of this structure might provide more sensitive preclinical markers of AD, provided its anatomic location is known. The purpose of this study was therefore to define the anatomic location of the TR with respect to the collateral sulcus. Gallyas-stained coronal temporal lobe sections of consecutively autopsied patients were inspected and included in this study if the staining clearly marked the TR ( n = 64). The number and depths of the collateral sulci were related to the lengths and placement of the TRs. Two patterns emerged: (1) if two discontinuous collateral sulci were present, the TR straddled the more medial and shallow collateral sulcus (8%); (2) if one collateral sulcus was present (91%), the TR included its medial bank. We provide more detailed descriptions of the lateral and medial TR borders for use in volumetric imaging studies.
Mutations in the amyloid precursor protein (APP) gene cause early-onset familial Alzheimer disease (AD) by affecting the formation of the amyloid β (Aβ ) peptide, the major constituent of AD plaques. ...We expressed human APP751 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 670/671 combined with the V7171 mutation causes Aβ 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, inflammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunore-active 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 Aβ in the pathogenesis of the disease.
Background A 66-year-old man presented with a 3-year history of personality changes marked by increasing apathy, social withdrawal and deficits in complex attention, and a 1-year history of ...progressive memory problems and difficulties in planning and carrying out complex tasks. Investigations Three neuropsychological examinations over 2 years, neurological examination, routine laboratory tests, brain MRI, single-photon emission CT scan, genetic analyses, and neuropathological examination. Diagnosis A clinical diagnosis of frontal-variant frontotemporal dementia was superseded by postmortem neuropathological evidence, which established a diagnosis of frontal-variant Alzheimer's disease. Management The patient and his spouse were referred for counseling, and the patient was referred for follow-up examinations.
Glial fibrillary acidic protein, GFAP, is a major intermediate filament protein of glial cells and major cytoskeletal structure in astrocytes. The entorhinal cortex has a key role in memory function ...and is one of the first brain areas to reveal hallmark structures of Alzheimer's disease and therefore provides an ideal tissue to investigate incipient neurodegenerative changes. Here we have analyzed age‐ and disease‐related occurrence and composition of GFAP in the human entorhinal cortex by using one‐ and two‐dimensional electrophoresis, Western blots and immunocytochemistry combined with confocal microscopy. A novel monoclonal antibody, GF‐02, was characterized that mainly reacted with intact GFAP molecules and indicated that more acidic and soluble GFAP forms were also more susceptible to degradation. GFAP and vimentin increased with aging and in Alzheimer's disease (AD). Two‐dimensional electrophoresis and Western blots revealed a complex GFAP pattern, both in aging and AD with different modification and degradation forms. Immunohistochemistry indicated that reactive astrocytes mainly accumulated in relation to neurofibrillary tangles and senile plaques in deeper entorhinal cortex layers. GFAP may be used as an additional but not exclusive diagnostic tool in the evaluation of neurodegenerative diseases because its levels change with age and respond to senile plaque and tangle formation.
Protein phosphatase 2A (PP2A) is a multimeric enzyme, containing a catalytic subunit complexed with two regulatory subunits. The catalytic subunit PP2A C is encoded by two distinct and unlinked ...genes, termed Cα and Cβ . The specific function of these two catalytic subunits is unknown. To address the possible redundancy between PP2A and related phosphatases as well as between Cα and Cβ , the Cα subunit gene was deleted by homologous recombination. Homozygous null mutant mice are embryonically lethal, demonstrating that the Cα subunit gene is an essential gene. As PP2A exerts a range of cellular functions including cell cycle regulation and cell fate determination, we were surprised to find that these embryos develop normally until postimplantation, around embryonic day 5.5/6.0. While no Cα protein is expressed, we find comparable expression levels of PP2A C at a time when the embryo is degenerating. Despite a 97% amino acid identify, Cβ cannot completely compensate for the absence of Cα . Degenerated embryos can be recovered even at embryonic day 13.5, indicating that although embryonic tissue is still capable of proliferating, normal differentiation is significantly impaired. While the primary germ layers ectoderm and endoderm are formed, mesoderm is not formed in degenerating embryos.
The superior colliculus (SC) is believed to play an important role in sensorimotor integration and orienting behavior. It is classically divided into superficial layers predominantly containing ...visual neurons and deep layers containing multisensory and premotor neurons. Investigations of intrinsic connectivity within the SC in non-human species initially led to controversy regarding the existence of interlaminar connections between superficial and deep layers. It now seems more likely that such connections exist in a number of species, including non-human primates. In the latter, anatomical data concerning intrinsic SC connectivity are restricted to a limited number of intracellularly labeled neurons. No studies have been conducted to investigate the existence of intrinsic connections of human SC. In the present study, DiI (1,1'-dioctadecyl-3,3,3',3'- tetramethylindocarbocyanine perchlorate) and BDA (biotinylated dextran amine) were two tracers used in post-mortem human brains to examine intrinsic SC connections. Injections into the superficial layers revealed tangential connections within superficial layers and radial superficial-layer to deep-layer connections. Within superficial layers, horizontal connections were found over the entire rostro-caudal axis and were mostly directed laterally, i.e. toward the brachium of the inferior colliculus. Superficial-layer to deep-layer connections were more prominent in sections containing the injection site or located close to it. In these sections, an axon bundle having roughly the same diameter as the injection site crossed all deep layers, and individual axons displayed en passant or terminal boutons. The present results suggest that intrinsic connections within superficial layers and radial superficial-layers to deep-layers exist in human SC. The putative roles of these connections are discussed with regard to visual receptive field organization, as well as visuomotor and multisensory integration.
Spinocerebellar ataxia (SCA) type 10, an autosomal dominant disease characterized by cerebellar ataxia, is caused by a novel
pentanucleotide (ATTCT) repeat expansion in the SCA10 gene. Although ...clinical features of the disease are well characterized,
nothing is known so far about the affected SCA10 gene product, ataxin-10 (Atx-10). We have cloned the rat SCA10 gene and expressed
the corresponding protein in HEK293 cells. Atx-10 has an apparent molecular mass of â¼55 kDa and belongs to the family of armadillo
repeat proteins. In solution, it tends to form homotrimeric complexes, which associate via a tip-to-tip contact with the concave
sides of the molecules facing each other. Atx-10 immunostaining of mouse and human brain sections revealed a predominantly
cytoplasmic and perinuclear localization with a clear restriction to olivocerebellar regions. Knock down of SCA10 in primary
neuronal cells by small interfering RNAs resulted in an increased apoptosis of cerebellar neurons, arguing for a loss-of-function
phenotype in SCA10 patients.
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