β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease

Abstract

Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of ␤-amyloid and ␣-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human ␤-amyloid peptides, ␣-synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before ␣-synuclein singly tg mice, and showed prominent agedependent degeneration of cholinergic neurons and presynaptic terminals. They also had more ␣-synuclein-immunoreactive neuronal inclusions than ␣-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in ␣-synuclein singly tg mice. ␤-Amyloid peptides promoted aggregation of ␣-synuclein in a cell-free system and intraneuronal accumulation of ␣-synuclein in cell culture. ␤-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of ␣-synuclein and exacerbating ␣-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of ␤-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.A ging is a major risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and the number of people with these conditions is increasing rapidly. In the United States alone, an estimated 4 million people have AD and at least one million have PD. Within the next 40-50 years, these numbers are projected to increase to over 8 million for AD and to 4 million for PD. Each neurodegenerative disease appears to have a predilection for specific brain regions and cell populations. However, human cases with clinical and neuropathological features of both AD and PD (1-3) raise the possibility that these diseases involve overlapping pathways.Many AD patients develop signs of PD and some PD patients become demented (3). Both diseases are associated with degeneration of neurons and interneuronal synaptic connections, depletion of specific neurotransmitters, and abnormal accumulation of misfolded proteins, whose precursors participate in normal central nervous system functions (4-11). The ␤-amyloid protein precursor (APP) and ␣-synuclein (SYN) are expressed abundantly in synapses, are well conserved across species, and have been implicated in neural plasticity, learning, and memory (6,7,12). Mutations in human APP (hAPP) that increase production of hAPP-derived ␤-amyloid peptides (A␤) cause autosomal dominant forms of familial AD (FAD) (11), and expression of FAD-mutant hAPPs in neurons of transgenic (tg) mice results in the age-dependent development of AD-like central nervous system alterations (13-17). Mutations in human SYN (hSYN) that enhance hSYN aggregation have bee...

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

“…We previously identified co‐pathogenic interactions between A β and SYN in hAPP/SYN doubly transgenic mice57 that may be relevant to the frequent co‐occurrence of DLB and AD pathology 58, 59, 60. Because clinical assessment alone cannot reliably detect the co‐occurrence of these pathologies,59 an obvious limitation of our study is the lack of autopsy confirmation of most cases we analyzed by chart review or EEG.…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…Furthermore, as these proteins may co-aggregate and/or regulate each other [29,30,[159][160][161], immunization against one of them could reduce the aggregation or toxic modification of the others. For example, immunization against Aβ might be helpful at reducing α-syn and tau if administered at early disease stages [62]; likewise, α-syn antibodies might also be helpful in AD [162], and immunization against tau might be useful for PD [161,163].…”

“…Remarkably, there is also evidence that these various protein aggregates can interact with each other [29]. For example, Aβ promotes the aggregation of α-syn and tau in AD and DLB [30,31], α-syn and tau interact in the brain of patients with PD and DLB [32,33], α-syn and Aβ can form hetero-oligomers [34,35], and α-syn can modulate the fibrillization state of Aβ [36].…”

Modèles animaux des maladies neuro-dégénératives

“…Le croisement de ces souris transgéniques α-synucléine avec des souris APP potentialise l'accumulation de l'α-synucléine, qui peut alors prendre un aspect fibrillaire [33]. Cette interaction entre pathologies Alzheimer et Parkinson, observée chez l'homme [34], reste mal comprise.…”