What could possibly go wrong with the use of BACE inhibitors for the prevention or treatment of AD?

The latest flurry of results from pharmaceutical companies showing that BACE inhibitors reduce the levels of amyloid-β in the brain has led to a renewed wave of optimism that this approach may lead to an effective treatment for AD, possibly even a cure. This optimism has been amplified by the recent report of a mutation in the APP gene, A673T, that reduces BACE activity and protects against AD (Jonsson et al., 2012).

We have recently suggested that there is a plausible explanation for the effect of the APP A673T mutation on AD rates that goes beyond the conventional wisdom of “less Aβ protects, more Aβ harms” involving a fine-tuning effect on Aβ levels by the A673T mutation that improves the adaptive response of APP to AD-causing brain stress (Castello and Soriano, 2012). In other words, there is likely a range of Aβ that optimizes the adaptive response of APP to brain stress, and the A673T mutation helps to maintain Aβ levels within that range.

It is very unlikely...  Read more

What could possibly go wrong with the use of BACE inhibitors for the prevention or treatment of AD?

The latest flurry of results from pharmaceutical companies showing that BACE inhibitors reduce the levels of amyloid-β in the brain has led to a renewed wave of optimism that this approach may lead to an effective treatment for AD, possibly even a cure. This optimism has been amplified by the recent report of a mutation in the APP gene, A673T, that reduces BACE activity and protects against AD (Jonsson et al., 2012).

We have recently suggested that there is a plausible explanation for the effect of the APP A673T mutation on AD rates that goes beyond the conventional wisdom of “less Aβ protects, more Aβ harms” involving a fine-tuning effect on Aβ levels by the A673T mutation that improves the adaptive response of APP to AD-causing brain stress (Castello and Soriano, 2012). In other words, there is likely a range of Aβ that optimizes the adaptive response of APP to brain stress, and the A673T mutation helps to maintain Aβ levels within that range.

It is very unlikely that any laboratory-led BACE manipulation may result in a better therapeutic outcome than what this mutation provides. Indeed, a reduction in Aβ levels through BACE inhibition that is too dramatic would compromise Aβ physiological function and have a catastrophic impact on neuronal function, even if there were no fears of potential BACE side effects, which is also an unlikely scenario (see, e.g., note of caution by Weihong Song above).

Overall, everything we know very strongly suggests that inhibiting BACE activity in the brain to treat AD may not be the most sensible way forward.

References:
Jonsson et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2000;488 ;96–99. Abstract

Castello MA, Soriano S. Rational heterodoxy: Cholesterol reformation of the amyloid doctrine. Ageing Res Rev. 2012 Jul 6. Abstract

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BACE1 inhibition is an important potential theurapeutic arm of the β amyloid clearance phenomenon in Alzheimer's which needs to be realized clinically.

However, another BACE1 inhibitor, 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...  Read more

BACE1 inhibition is an important potential theurapeutic arm of the β amyloid clearance phenomenon in Alzheimer's which needs to be realized clinically.

However, another BACE1 inhibitor, 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 “Borrelia 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).

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

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