Accumulation of the synaptic protein ␣-synuclein (␣-syn) is a hallmark of Parkinson's disease (PD) and Lewy body disease (LBD),

Alzheimer's disease (AD), an incurable, progressive neurodegenerative disorder, is the most common form of dementia. Therapeutic options have been elusive due to the inability to deliver proteins across the blood-brain barrier (BBB). In order to improve the therapeutic potential for AD, we utilized a promising new approach for delivery of proteins across the BBB. We generated a lentivirus vector expressing the amyloid β-degrading enzyme, neprilysin, fused to the ApoB transport domain and delivered this by intra-peritoneal injection to amyloid protein precursor (APP) transgenic model of AD. Treated mice had reduced levels of Aβ, reduced plaques and increased synaptic density in the CNS. Furthermore, mice treated with the neprilysin targeting the CNS had a reversal of memory deficits. Thus, the addition of the ApoB transport domain to the secreted neprilysin generated a non-invasive therapeutic approach that may be a potential treatment in patients with AD.

Background: Proteolytic degradation has emerged as a key pathway involved in controlling levels of the Alzheimer's disease (AD)-associated amyloid-β (Aβ) peptide in the brain. The endopeptidase, neprilysin, has been implicated as a major Aβ degrading enzyme in mice and humans. Previous short and intermediate term studies have shown the potential therapeutic application of neprilysin by delivering this enzyme into the brain of APP transgenic mice using gene transfer with viral vectors. However the effects of long-term neprilysin gene transfer on other aspects of Aβ associated pathology have not been explored yet in APP transgenic mice.

The endopeptidase neprilysin (NEP) is a major amyloid-␤ (A␤) degrading enzyme and has been implicated in the pathogenesis

Neuropeptide Y (NPY) is one of the most abundant protein transmitters in the central nervous system with roles in a variety of biological functions including: food intake, cardiovascular regulation, cognition, seizure activity, circadian rhythms, and neurogenesis. Reduced NPY and NPY receptor expression is associated with numerous neurodegenerative disorders including Alzheimer disease (AD). To determine whether replacement of NPY could ameliorate some of the neurodegenerative and behavioral pathology associated with AD, we generated a lentiviral vector expressing NPY fused to a brain transport peptide (apoB) for widespread CNS delivery in an APP-transgenic (tg) mouse model of AD. The recombinant NPY-apoB effectively reversed neurodegenerative pathology and behavioral deficits although it had no effect on accumulation of A␤. The subgranular zone of the hippocampus showed a significant increase in proliferation of neural precursor cells without further differentiation into neurons. The neuroprotective and neurogenic effects of NPY-apoB appeared to involve signaling via ERK and Akt through the NPY R1 and NPY R2 receptors. Thus, widespread CNS-targeted delivery of NPY appears to be effective at reversing the neuronal and glial pathology associated with A␤ accumulation while also increasing NPC proliferation. Overall, increased delivery of NPY to the CNS for AD might be an effective therapy especially if combined with an anti-A␤ therapeutic.Neuropeptide Y (NPY), 2 one of the most abundant neuropeptides in the central and peripheral nervous system is synthesized in neurons and transported to pre-and post-synaptic vesicles where it is secreted (1). NPY is produced as preproenzyme that is processed first by removal of the secretory signal in the endoplasmic reticulum to produce the pro-NPY and then by the peptidase convertase to generate NPY(1-39). Further editing by peptidase enzymes generates the mature NPY(1-36) (2).This mature form binds primarily to three different receptors in the rodent brain, NPY R1, NPY R2, and NPY R5; which are all seven transmembrane receptors (3). Upon binding to the receptor, signaling pathways involve the activation of the G i /G o receptors and inhibition of cAMP synthesis followed by signaling through protein kinase C, mitogen-activated protein kinase (MAPK), inositol trisphosphate, and extracellular signal related kinase (ERK) (3).NPY is associated with a variety of biologic functions including: food intake, cardiovascular regulation, cognition, seizure activity, circadian rhythms, and neurogenesis (4). Alterations in NPY have been associated with many neurodegenerative disorders including Downs syndrome (5), Huntington disease (6), and epilepsy (1), and reduced NPY levels have been reported in the CNS in Alzheimer disease (AD). Immunocytochemical studies have shown decreased NPY (7-12) and NPY receptors (13) immunoreactivity in the hippocampus of AD patients and NPY accumulation in dystrophic neurites around the amyloid plaques (14). In addition, reduced levels of NPY in the plasma (1...

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