Alzheimer disease is a major cause of cognitive failure, and a pathogenically related but more subtle process accounts for many cases of mild memory symptoms in older humans. Insoluble fibrillar plaques of amyloid β-proteins (Aβ) and neurofibrillary deposits of hyperphosphorylated tau proteins are the diagnostic lesions of AD, but their temporal mechanistic relationship has long been debated. The recent recognition that small, diffusible oligomers may be the principal bioactive form of Aβ raises the key question of whether these are sufficient to initiate cytoskeletal change and neurite degeneration. A few studies have examined the effects of oligomers of synthetic Aβ peptides of one defined length at supraphysiological concentrations, but the existence of such assemblies in the AD brain is not established. Here, we isolated Aβ dimers, the most abundant form of soluble oligomer detectable in the human brain, from the cortices of typical AD subjects and found that at subnanomolar concentrations, they first induced hyperphosphorylation of tau at AD-relevant epitopes in hippocampal neurons and then disrupted the microtubule cytoskeleton and caused neuritic degeneration, all in the absence of amyloid fibrils. Application of pure, synthetic dimers confirmed the effects of the natural AD dimers, although the former were far less potent. Knocking down endogenous tau fully prevented the neuritic changes, whereas overexpressing human tau accelerated them. Coadministering Aβ N-terminal antibodies neutralized the cytoskeletal disruption. We conclude that natural dimers isolated from the AD brain are sufficient to potently induce AD-type tau phosphorylation and then neuritic dystrophy, but passive immunotherapy mitigates this.A lzheimer disease (AD) and its harbinger, mild cognitive impairment-amnestic type, comprise the most prevalent latelife cognitive disorder in humans. The aging of the population in developed nations has led to predictions that the prevalence of Alzheimer-type dementia will rise substantially during the next few decades. Intensive research over almost 30 y has led to the hypothesis that progressive cerebral accumulation of the 42-residue amyloid β-protein (Aβ) may precipitate the synaptic dysfunction and cytoskeletal changes that underlie the symptoms of AD (1). Although insoluble amyloid plaques are one of the two neuropathological hallmarks of AD, recent studies suggest that these are in equilibrium with small, diffusible oligomers of Aβ that may serve as the principal synaptotoxic form of the protein (2).A major unresolved question about AD pathogenesis is the relationship of Aβ deposits to the other cardinal lesion of the disease, the neurofibrillary tangle. These two lesions occur together in virtually all cases of AD, but whether Aβ build-up is directly responsible for the neurofibrillary degeneration of AD is the subject of debate. Specifically, the growing experimental evidence that key features of the AD phenotype, such as dendritic spine loss, altered hippocampal synaptic plasticity, and impa...

In Alzheimer's disease, dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Numerous studies report that hippocampal LTP can be inhibited by soluble oligomers of amyloid β-protein (Aβ), but the synaptic elements that mediate this effect remain unclear. We examined field excitatory postsynaptic potentials and whole-cell recordings in wild-type mouse hippocampal slices. Soluble Aβ oligomers from three distinct sources (cultured cells, AD cortex or synthetic peptide) inhibited LTP, and this was prevented by the selective NR2B inhibitors, Ifenprodil and Ro 25-6981. Soluble Aβ enhanced NR2B-mediated NMDA currents and extrasynaptic responses; these effects were mimicked by the glutamate reuptake inhibitor, TBOA. Downsteam, an Aβ-mediated rise in p38 MAPK activation was followed by downregulation of CREB protein, and LTP impairment was prevented by inhibitors of p38 MAPK or calpain. Thus, soluble Aβ oligomers at low nanomolar levels present in AD brain increase activation of extrasynaptic NR2B-containing receptors, thereby impairing synaptic plasticity.

Copy number mutations implicate excess production of α-synuclein as a possibly causative factor in Parkinson’s disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the β2-adrenoreceptor (β2AR) is a regulator of the α-synuclein gene (SNCA). β2AR ligands modulate SNCA transcription through histone 3 lysine 27 acetylation of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the β2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a β2AR antagonist correlated with increased risk. β2AR activation protected model mice and patient-derived cells. Thus, β2AR is linked to transcription of α-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.