Mind how you go: The current strategies for the development of therapies for Alzheimer's disease are very diverse. Particular attention is given to the search for inhibitors (see picture for two examples) of the proteolytic enzyme beta- and gamma-secretase, which inhibits the cleavage of the amyloid precursor proteins into amyloid beta peptides, from which the disease-defining deposits of plaque in the brains of Alzheimer's patients originates.Research on senile dementia and Alzheimer's disease covers an extremely broad range of scientific activities. At the recent international meeting of the Alzheimer's Association (ICAD 2008, Chicago) more than 2200 individual scientific contributions were presented. The aim of this Review is to give an overview of the field and to outline its main areas, starting from behavioral abnormalities and visible pathological findings and then focusing on the molecular details of the pathology. The "amyloid hypothesis" of Alzheimer's disease is given particular attention, since the majority of the ongoing therapeutic approaches are based on its theoretical framework.

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...

(Oligodendro)glial cytoplasmic inclusions composed of α-synuclein (αSYN) characterize multiple system atrophy (MSA). Mature oligodendrocytes (OLs) do not normally express αSYN, so MSA pathology may arise from aberrant expression of αSYN in OLs. To study pathological deposition of αSYN in OLs, transgenic mice were generated in which human wild-type αSYN was driven by a proteolipid protein promoter. Transgenic αSYN was detected in OLs but no other brain cell type. At the light microscopic level, the transgenic αSYN profiles resembled glial cytoplasmic inclusions. Strikingly, the diagnostic hyperphosphorylation at S129 of αSYN was reproduced in the transgenic mice. A significant proportion of the transgenic αSYN was detergent insoluble, as in MSA patients. The histological and biochemical abnormalities were specific for the disease-relevant αSYN because control green fluorescent protein was fully soluble and evenly distributed throughout OL cell bodies and processes. Thus, ectopic expression αSYN in OLs might initiate salient features of MSA pathology.

Alzheimer disease amyloid ␤-peptide (A␤) is generated via proteolytic processing of the ␤-amyloid precursor protein by ␤-and ␥-secretase. ␥-Secretase can be blocked by selective inhibitors but can also be modulated by a subset of non-steroidal antiinflammatory drugs, including sulindac sulfide. These drugs selectively reduce the generation of the aggregation-prone 42-amino acid A␤ 42 and concomitantly increase the levels of the rather benign A␤ 38 . Here we show that A␤ 42 and A␤ 38 generation occur independently from each other. The amount of A␤ 42 produced by cells expressing 10 different familial Alzheimer disease (FAD)-associated mutations in presenilin (PS) 1, the catalytic subunit of ␥-secretase, appeared to correlate with the respective age of onset in patients. However, A␤ 38 levels did not show a negative correlation with the age of onset. Modulation of ␥-secretase activity by sulindac sulfide reduced A␤ 42 in the case of wild type PS1 and two FAD-associated PS1 mutations (M146L and A285V). The remaining eight PS1 FAD mutants showed either no reduction of A␤ 42 or only rather subtle effects. Strikingly, even the mutations that showed no effect on A␤ 42 levels allowed a robust increase of A␤ 38 upon treatment with sulindac sulfide. Similar observations were made for fenofibrate, a compound known to increase A␤ 42 and to decrease A␤ 38 . For mutants that predominantly produce A␤ 42 , the ability of fenofibrate to further increase A␤ 42 levels became diminished, whereas A␤ 38 levels were altered to varying extents for all mutants analyzed. Thus, we conclude that A␤ 38 and A␤ 42 production do not depend on each other. Using an independent non-steroidal anti-inflammatory drug derivative, we obtained similar results for PS1 as well as for PS2. These in vitro results were confirmed by in vivo experiments in transgenic mice expressing the PS2 N141I FAD mutant. Our findings therefore have strong implications on the selection of transgenic mouse models used for screening of the A␤ 42 -lowering capacity of ␥-secretase modulators. Furthermore, human patients with certain PS mutations may not respond to ␥-secretase modulators.Alzheimer disease is the most abundant form of dementia, and increasing numbers of patients are to be expected in the near future. Amyloid ␤-peptide (A␤) 5 is a central player in the disease pathology. Originally it was purified as the building block of the disease-defining amyloid plaques. Now it is becoming clear that amyloid plaques are probably not the major neurotoxic entity in the disease rather this is an assembly of soluble oligomeric A␤ species (1). These assemblies initiate the so-called amyloid cascade and finally induce abnormal phosphorylation of tau and subsequent formation of paired helical filaments (2). A␤ is generated by proteolytic processing of the ␤-amyloid precursor protein (APP). Two proteases, ␤-secretase and ␥-secretase, perform the cleavages on the N and C termini of the A␤ domain, respectively (3). ␤-Secretase is a conventional aspartyl protease, whereas ␥-secretase i...

alpha-Synuclein (alpha-SYN) is deposited in intraneuronal cytoplasmic inclusions (Lewy bodies, LBs) characteristic for Parkinson's disease (PD) and LB dementias. alpha-SYN forms LB-like fibrils in vitro, in contrast to its homologue beta-SYN. Here we have investigated the solubility of SYNs in human LB diseases and in transgenic mice expressing human wild-type and PD-associated mutant [A30P]alpha-SYN driven by the brain neuron-specific promoter, Thy1. Distinct alpha-SYN species were detected in the detergent-insoluble fractions from brains of patients with PD, dementia with LBs, and neurodegeneration with brain iron accumulation type 1 (formerly known as Hallervorden-Spatz disease). Using the same extraction method, detergent-insolubility of human alpha-SYN was observed in brains of transgenic mice. In contrast, neither endogenous mouse alpha-SYN nor beta-SYN were detected in detergent-insoluble fractions from transgenic mouse brains. The nonamyloidogenic beta-SYN was incapable of forming insoluble fibrils because amino acids 73 to 83 in the central region of alpha-SYN are absent in beta-SYN. In conclusion, the specific accumulation of detergent-insoluble alpha-SYN in transgenic mice recapitulates a pivotal feature of human LB diseases.