Aβ Immunotherapy Protects Morphology and Survival of Adult-Born Neurons in Doubly Transgenic APP/PS1 Mice

Abstract

The hippocampus is heavily affected by progressive neurodegeneration and ␤-amyloid pathology in Alzheimer's disease (AD). The hippocampus is also one of the few brain regions that generate new neurons throughout adulthood. Because hippocampal neurogenesis is regulated by both endogenous and environmental factors, we determined whether it benefits from therapeutic reduction of ␤-amyloid peptide (A␤)-related toxicity induced by passive A␤ immunotherapy. A␤ immunotherapy of 8 -9-month-old mice expressing familial AD-causing mutations in the amyloid precursor protein and presenilin-1 genes with an antibody against A␤ decreased compact ␤-amyloid plaque burden and promoted survival of newly born neurons in the hippocampal dentate gyrus. As these neurons matured, they exhibited longer dendrites with more complex arborization compared with newly born neurons in control-treated transgenic littermates. The newly born neurons showed signs of functional integration indicated by expression of the immediate-early gene Zif268 in response to exposure to a novel object. A␤ immunotherapy was associated with higher numbers of synaptophysin-positive synaptic boutons. Labeling dividing progenitor cells with a retroviral vector encoding green fluorescent protein (GFP) showed that A␤ immunotherapy restored the impaired dendritic branching, as well as the density of dendritic spines in new mature neurons. The presence of cellular prion protein (PrP c ) on the dendrites of the GFP ϩ newly born neurons is compatible with a putative role of PrP c in mediating A␤-related toxicity in these cells. In addition, passive A␤ immunotherapy was accompanied by increased angiogenesis. Our data establish that passive A␤ immunotherapy can restore the morphological maturation of the newly formed neurons in the adult hippocampus and promote angiogenesis. These findings provide evidence for a role of A␤ immunotherapy in stimulating neurogenesis and angiogenesis in transgenic mouse models of AD, and they suggest the possibility that A␤ immunotherapy can recover neuronal and vascular functions in brains with ␤-amyloidosis.

Amyloid-β Peptide-specific DARPins as a Novel Class of Potential Therapeutics for Alzheimer Disease

“…DARPin D23 at 50 nM was preincubated with a 50-fold molar excess of the peptide fragments A␤(Ϫ4 -6), A␤(Ϫ3-7), A␤(Ϫ2-8), A␤(Ϫ1-9), A␤(1-8), A␤(2-11), A␤ (3)(4)(5)(6)(7)(8)(9)(10)(11)(12), A␤(4 -13), A␤ (5)(6)(7)(8)(9)(10)(11)(12)(13)(14), A␤(6 -15) (peptides&elephants, Potsdam, Germany), A␤(1-11), A␤ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), A␤ (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)…”

“…Biochemical and Histochemical Analyses-Brains from treated mice were obtained as described previously (25). The right hemibrain was homogenized using a sequential extraction protocol using a glass-Teflon homogenizer (20 strokes, 315 rpm) in RIPA buffer containing complete protease inhibitor tablets (Sigma).…”

“…Histochemistry-Thioflavine S staining was done according to a previously published protocol (25). All chemicals were obtained from Sigma.…”

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

“…Different therapeutic strategies attempting to reduce brain burden of protein aggregates have been developed [5] including: i) direct targeting of misfolded proteins; ii) drawing the protein excess out of the brain by peripheral administration of oligomer-binding agents (the so-called "sink effect") [6][7][8]; iii) upregulating molecular chaperones or proteins involved in aggregate clearance [5]; iv) targeting posttranslational modifications that promote protein misfolding and aggregation [5]; v) the use of nanotechnological devices, and in particular multifunctional liposomes [9,10]. Herein, current literature on compounds able to prevent/disrupt protein aggregation, thus removing toxic oligomers, will be summarised [11].…”

Dietary Nucleotides in Neurodegenerative Diseases

“…In general, adenosine receptors in synapses, induced by nucleotides or other similar substances such as caffeine can help prevent loss of memory associated with neurodegenerative diseases. In addition, in these conditions of inflammation cell renewal is blocked, hindering the recovery of the affected areas [18,19]. Encouraged by these studies, the industry has begun to design and test specific diets for people with neurodegenerative diseases risk, especially for Alzheimer's disease.…”