The amyloid prevention trial of antibodies has not proven successful at least in the patients studied so far. Perhaps with new imaging techiques for amyloid, milder forms of cognitive impairment in the Alzheimer's spectrum will be diagnosed and enrolled in such clinic trials.
Another avenue of therapy is now focusing on BACE1 inhibitors.
At the Alzheimer’s Association International Conference held 14-19 July 2012 in Vancouver, Canada, three companies reported promising Phase 1 data on brain-penetrant compounds that block BACE1 activity. The protease cuts amyloid precursor protein (APP) to kick off production of the Aβ peptides believed to be a molecular culprit of Alzheimer’s disease. BACE1 inhibition is an important potential theurapeutic arm of the β amyloid clearance phenomenon in Alzheimer's which needs to be realized clinically.
As dicussed in a recent Alzheimer's research forum, a BACE1 inhibitor, minocycline, a antibiotic was dicussed.
Minocycline, which is also neuroprotective and is already an approved therapeutic agent, is now undergoing trials in cognitively normal individuals and patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD) at Huntington Medical Research Institute. Patients and controls will undergo clinical screening, neuropsychological tests, blood and urine analyses, quantitative magnetic resonance imaging (MRI), and 1H and 13C magnetic resonance spectroscopy (MRS). Each individual will receive minocycline oral administration for four weeks initially, after which MRI, MRS, and neuropsych results will be recorded. If no adverse side effects occur, subjects will continue minocycline administration for an additional five months.
A study by Ferretti demonstrated recently that minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE1 in a transgenic model of Alzheimer's disease-like amyloid pathology (Ferretti et al., 2012).
There are a small group of Alzforum members who are interested in the emerging role of pathogens in Alzheimer's disease, and feel that β amyloid clearance problems may be the result of pathogenic inflammation (spirochetal) with and without viruses.
Chronic spirochetal infection can cause slowly progressive dementia, cortical atrophy, and amyloid deposition in the atrophic form of general paresis. There is a significant association between Alzheimer's disease (AD) and various types of spirochetes (including the periodontal pathogen Treponemas and Borrelia burgdorferi), and other pathogens such as Chlamydophyla pneumoniae and herpes simplex virus type 1 (Miklossy, 2011). Miklossy’s lab at the University Medical School (CHUV), Lausanne, Switzerland, exposed mammalian glia and neuronal cells in vitro to Borrelia burgdorferi spirochetes and bacterial lipopolysaccharides. Morphological changes analogous to amyloid deposits were observed at two to eight weeks' exposure. Increased levels of β amyloid precursor protein and hyperphosphorylated tau were detected by Western blot (Miklossy et al., 2004).
Seven out of 10 brains from the Harvard McLean Brain Bank were positive for Borrelia DNA. Alan MacDonald demonstrated this, and feels â€োorrelia burgdorferi infection is the root cause of at least 70 percent of Alzheimer's disease, based on the detection of positive in-situ DNA hybridization results in the cytoplasmic granulovacuolar bodies of hippocampal neurons (with no positive signals detected in the nucleus) for flagellin B DNA sequences of Borrelia burgdorferi" (MacDonald, 2007).
A randomized controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease demonstrated that cognitive decline was statistically improved in the treatment arm over placebo (Loeb et al., 2004).
Minocycline protected basal forebrain cholinergic neurons from murine-p75-saporin immunotoxic lesioning in animal models (Hunter et al., 2004). Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models (Choi et al., 2007). Minocycline does not affect amyloid-β phagocytosis by human microglia cells. Minocycline attenuates the release of TNF-α by human microglia upon exposure to Aβ, SAP, and C1q (Familian et al., 2007).
A combination of combined therapy with minocycline or doxycycline and moderate magnetic fields which was found to have a temporary improvement in cognitive impairment in moderate Alzheimer's patients is proposed:
Moderate magnetic field therapy (0.5 Tesla) in 15 Alzheimer’s patients was demonstrated by this author in 2006 on the hypothesis that the outer protein of the Borrelia burgdorferi bacteria is strongly electron-negatively charged and will be repelled by the negative pole of a 0.5 Tesla electromagnet below and a positive pole above the patient's head. Cognition improved. However, this improvement was gradually lost from several weeks to six months in these patients in an open-label, IRB-approved pilot study. All patients had moderate to severe Alzheimer's disease (Nichols et al., 2006).
The mechanism may also be related to crosstalk between SMF and IL-6, as well as the upregulation or downregulation of over 2,600 genes (Wang et al., 2009).
References:
Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. J Neuroinflammation. 2012;9:62. Abstract
Miklossy J. Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med. 2011;13:e30. Abstract
Miklossy J, Khalili K, Gern L, Ericson RL, Darekar P, Bolle L, Hurlimann J, Paster BJ. Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease. J Alzheimers Dis. 2004 Dec;6(6):639-49; discussion 673-81. Abstract
MacDonald AB. Alzheimer's neuroborreliosis with trans-synaptic spread of infection and neurofibrillary tangles derived from intraneuronal spirochetes. Med Hypotheses. 2007;68(4):822-5. Abstract
Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith CH, Mahony J, Smith S, Borrie M, Decoteau E, Davidson W, McDougall A, Gnarpe J, O'DONNell M, Chernesky M. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease. J Am Geriatr Soc. 2004 Mar;52(3):381-7. Abstract
Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC. Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning. Eur J Neurosci. 2004 Jun;19(12):3305-16. Abstract
Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Kim HS, Park CH, Jeong YH, Yoo J, Lee JP, Chang KA, Kim S, Suh YH. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models. Neuropsychopharmacology. 2007 Nov;32(11):2393-404. Abstract
Familian A, Eikelenboom P, Veerhuis R. Minocycline does not affect amyloid beta phagocytosis by human microglial cells. Neurosci Lett. 2007 Apr 6;416(1):87-91. Abstract
Nichols et al. Medical Hypothesis; elctromagnetic field therapy using Magnetic Molecular Energising (MME) and Antibiotic Therapy: A Pilot Study. 31/01/2006. E pub; European Biology and Bioelectromagnetics.
Wang Z, Sarje A, Che PL, Yarema KJ. Moderate strength (0.23-0.28 T) static magnetic fields (SMF) modulate signaling and differentiation in human embryonic cells. BMC Genomics. 2009;10:356. Abstract