The pathologies occurring in Alzheimer disease (AD) are curious because of their overlap with other disorders. Although accumulation of Aβ is most commonly associated with AD, neuritic plaques are also observed in Parkinson dementia, diffuse Lewy body diseases, and other less common disorders. Similarly, tau inclusions occur in AD and frontotemporal dementia (as well as other less common diseases), and tau haplotypes are implicated in Parkinson disease. α-synuclein inclusions also occur in multiple diseases including Parkinson disease, diffuse Lewy body disease, and even AD. Prior work by Eliezer Masliah’s group produced a double-transgenic cross expressing both APP and α-synuclein, and showed enhanced accumulation of α-synuclein inclusions (Masliah et al., 2001). Similarly, John Trojanowski, Virginia Lee, and colleagues showed enhanced neurodegeneration in tau mice expressing mutant human α-synuclein (Giasson et al., 2003). The current manuscript from Frank LaFerla’s group, by Clinton et al., now pushes this idea a step further by combining his triple-transgenic model (3xTg-AD),...  Read more

The pathologies occurring in Alzheimer disease (AD) are curious because of their overlap with other disorders. Although accumulation of Aβ is most commonly associated with AD, neuritic plaques are also observed in Parkinson dementia, diffuse Lewy body diseases, and other less common disorders. Similarly, tau inclusions occur in AD and frontotemporal dementia (as well as other less common diseases), and tau haplotypes are implicated in Parkinson disease. α-synuclein inclusions also occur in multiple diseases including Parkinson disease, diffuse Lewy body disease, and even AD. Prior work by Eliezer Masliah’s group produced a double-transgenic cross expressing both APP and α-synuclein, and showed enhanced accumulation of α-synuclein inclusions (Masliah et al., 2001). Similarly, John Trojanowski, Virginia Lee, and colleagues showed enhanced neurodegeneration in tau mice expressing mutant human α-synuclein (Giasson et al., 2003). The current manuscript from Frank LaFerla’s group, by Clinton et al., now pushes this idea a step further by combining his triple-transgenic model (3xTg-AD), which develops Aβ and tau inclusions, with an α-synuclein model.

The quadruple-transgenic mice show a striking increase in accumulation of all three types of inclusions—Aβ, tau, and α-synuclein. The cognitive deficits also develop at an accelerated pace. One of the more striking aspects of the work is the location of the inclusions that form. The primary location of the α-synuclein inclusions shifts from brain stem in the mono-transgenic α-synuclein mouse to cortex and subiculum in the DLB-AD mouse. The shift in gross localization of the α-synuclein combined with the acceleration of cognitive decline highlights the interactions among these different types of inclusions. The accelerated neurodegeneration also emphasizes the additive damage associated with increasing burden of inclusions. Whether the additive damage reflects a direct mechanistic interaction of neurodegenerative pathways contributed by each type of inclusion or simply the additive burden of increased cumulative damage remains to be determined.

Although the combined effects of the inclusions is to produce additive degenerative effects, one of the surprising observations is that the tau and α-synuclein inclusions don’t show strong colocalization within neurons. Both form distinct and separate inclusions. This observation is reminiscent of observations by Giasson and colleagues, and by my group (Frasier et al., 2005), showing the presence of phosphorylated tau in brains of α-synuclein overexpressing mice, but also showing that the phospho-tau and α-synuclein accumulated in a different set of neurons (Frasier et al., 2005; Giasson et al., 2003). These observations raise a classic theme in neurodegenerative research—that of selective neuronal vulnerability. It remains unclear why specific inclusions form in particular sets of neurons, and in the case of LaFerla’s quadruple-transgenic mice, why one set of neurons might develop tau pathology while another develops α-synuclein pathology. Regardless of the ultimate answers, the model put forth by Clinton et al. will go a long way toward providing tools allowing us to investigate these questions.

References:
Frasier M, Walzer M, McCarthy L, Magnuson D, Lee JM, Haas C, Kahle P, Wolozin B. Tau phosphorylation increases in symptomatic mice overexpressing A30P alpha-synuclein. Exp Neurol. 2005 Apr;192(2):274-87. Abstract

Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 2003 Apr 25;300(5619):636-40. Abstract

Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L. beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12245-50. Abstract

View all comments by Benjamin Wolozin

This elegant study by Scott et al. takes advantage of primary neuron cultures from α-synuclein-GFP-transgenic mice to examine the effects of modest α-synuclein overexpression on presynaptic proteins. They find convincing evidence that α-synuclein can diminish levels of several critical presynaptic proteins involved in exocytosis and endocytosis. The authors also detect significant reductions in miniEPSC frequency, diminished presynaptic exocytosis, and altered vesicle size by EM in α-synuclein-overexpressing neurons. Thus, physiologically relevant increases in α-synuclein produce robust functional consequences that closely mimic those observed in animal models of endocytic protein deficiency.

The authors point out that similar effects on presynaptic proteins have recently been shown following Aβ oligomer exposure (Parodi et al., 2010), suggesting a possible common mechanism of synaptic dysfunction between AD and synucleinopathies. It is intriguing to speculate that this potential shared mechanism of synaptic dysfunction may play...  Read more

This elegant study by Scott et al. takes advantage of primary neuron cultures from α-synuclein-GFP-transgenic mice to examine the effects of modest α-synuclein overexpression on presynaptic proteins. They find convincing evidence that α-synuclein can diminish levels of several critical presynaptic proteins involved in exocytosis and endocytosis. The authors also detect significant reductions in miniEPSC frequency, diminished presynaptic exocytosis, and altered vesicle size by EM in α-synuclein-overexpressing neurons. Thus, physiologically relevant increases in α-synuclein produce robust functional consequences that closely mimic those observed in animal models of endocytic protein deficiency.

The authors point out that similar effects on presynaptic proteins have recently been shown following Aβ oligomer exposure (Parodi et al., 2010), suggesting a possible common mechanism of synaptic dysfunction between AD and synucleinopathies. It is intriguing to speculate that this potential shared mechanism of synaptic dysfunction may play a role in the acceleration of cognitive decline and aggressive disease course in patients and transgenic mice that co-exhibit both AD and Lewy body pathologies (Olchney et al., 1998; Clinton et al., 2010).

View all comments by Mathew Blurton-Jones