Anti-α-synuclein immunotherapy reduces α-synuclein propagation in the axon and degeneration in a combined viral vector and transgenic model of synucleinopathy

Abstract

Neurodegenerative disorders such as Parkinson’s Disease (PD), PD dementia (PDD) and Dementia with Lewy bodies (DLB) are characterized by progressive accumulation of α-synuclein (α-syn) in neurons. Recent studies have proposed that neuron-to-neuron propagation of α-syn plays a role in the pathogenesis of these disorders. We have previously shown that antibodies against the C-terminus of α-syn reduce the intra-neuronal accumulation of α-syn and related deficits in transgenic models of synucleinopathy, probably by abrogating the axonal transport and accumulation of α-syn in in vivo models. Here, we assessed the effect of passive immunization against α-syn in a new mouse model of axonal transport and accumulation of α-syn. For these purpose, non-transgenic, α-syn knock-out and mThy1-α-syn tg (line 61) mice received unilateral intra-cerebral injections with a lentiviral (LV)-α-syn vector construct followed by systemic administration of the monoclonal antibody 1H7 (recognizes amino acids 91-99) or control IgG for 3 months. Cerebral α-syn accumulation and axonopathy was assessed by immunohistochemistry and effects on behavior were assessed by Morris water maze. Unilateral LV-α-syn injection resulted in axonal propagation of α-syn in the contra-lateral site with subsequent behavioral deficits and axonal degeneration. Passive immunization with 1H7 antibody reduced the axonal accumulation of α-syn in the contra-lateral side and ameliorated the behavioral deficits. Together this study supports the notion that immunotherapy might improve the deficits in models of synucleinopathy by reducing the axonal propagation and accumulation of α-syn. This represents a potential new mode of action through which α-syn immunization might work.

The good and bad of therapeutic strategies that directly target α‐synuclein

“…In a following multicenter, randomized, double‐blind, placebo‐controlled trial, assessing multiple ascending doses of PRX002 in mild‐to‐moderate idiopathic PD patients aged 40 to 80 years (Hoehn and Yahr Stages 1–3), both single and multiple doses of this antibody resulted safe, were well tolerated, and produced robust binding of peripheral α‐syn as well as dose‐dependent increases of PRX002 in cerebrospinal fluid . Several other studies addressed the development of antibodies targeting α‐syn, including strategies targeting oligomeric forms, the C‐terminus of the protein, or exploiting passive immunization . Interestingly, some of these approaches were also found to efficiently reduce α‐syn propagation .…”

“…67 Several other studies addressed the development of antibodies targeting α-syn, 70,71 including strategies targeting oligomeric forms, [72][73][74] the C-terminus of the protein, 75 or exploiting passive immunization. [76][77][78] Interestingly, some of these approaches were also found to efficiently reduce α-syn propagation. 77 The combination of peptides specific to Aβ (AD02) and α-syn (PD-AFF1) was found to counteract the burden of these proteins, the associated neuroinflammation, and ameliorate behavioral deficits in DLB experimental models.…”

“…[76][77][78] Interestingly, some of these approaches were also found to efficiently reduce α-syn propagation. 77 The combination of peptides specific to Aβ (AD02) and α-syn (PD-AFF1) was found to counteract the burden of these proteins, the associated neuroinflammation, and ameliorate behavioral deficits in DLB experimental models. 79 Recently, a so-called "general amyloid interaction motif" was designed starting from a bacteriophage capsid protein and fused with human IgG to optimize an immune-based approach (NPT088 and NPT189) able to efficiently reduce the burden of amyloid deposition in models of amyloid and tau pathology and even synucleinopathy.…”

A Missense Point Mutation in Nerve Growth Factor (NGFR100W) Results in Selective Peripheral Sensory Neuropathy

“…The Morris water maze was used to evaluate spatial learning and memory as previously described (Spencer et al, 2017). A platform was placed in the center of one quadrant of the pool (diameter 180 cm).…”

“…To test if NGF +/fln mice at 18 month showed any deficit in their executive function, we used the Morris water maze ( Fig 11A) to evaluate spatial learning and memory (Spencer et al, 2017). Test mice were first trained to find a platform with a visible flag on days 1 to 3 and then a submerged hidden platform on days 4 to 7.…”