Abstract
Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of β-amyloid (Aβ) peptides may cause Alzheimer's disease (AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting Aβ have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating Aβ clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Aβ monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating Aβ formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases, β-secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of γ-secretase, the protease that regulates the last metabolic step generating Aβ, have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate α-secretase, the enzyme responsible for the nonamyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of Aβ aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-Aβ approaches in clinical testing, we will know in few years if the Aβ hypothesis of AD is correct.
| Original language | English |
|---|---|
| Pages (from-to) | 40-55 |
| Number of pages | 16 |
| Journal | Current Alzheimer Research |
| Volume | 7 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2010 |
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Keywords
- α-secretase activators
- β-amyloid
- β-secretase inhibitors
- γ-secretase inhibitors
- γ-secretase modulators
- Active immunotherapy
- Alzheimer's disease
- Passive immunotherapy
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
Cite this
Towards disease-modifying treatment of Alzheimer's disease : Drugs targeting β-amyloid. / Frisardi, V.; Solfrizzi, V.; Imbimbo, B. P.; Capurso, C.; D'Introno, A.; Colacicco, A. M.; Vendemiale, G.; Seripa, D.; Pilotto, A.; Capurso, A.; Panza, F.
In: Current Alzheimer Research, Vol. 7, No. 1, 01.2010, p. 40-55.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Towards disease-modifying treatment of Alzheimer's disease
T2 - Drugs targeting β-amyloid
AU - Frisardi, V.
AU - Solfrizzi, V.
AU - Imbimbo, B. P.
AU - Capurso, C.
AU - D'Introno, A.
AU - Colacicco, A. M.
AU - Vendemiale, G.
AU - Seripa, D.
AU - Pilotto, A.
AU - Capurso, A.
AU - Panza, F.
PY - 2010/1
Y1 - 2010/1
N2 - Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of β-amyloid (Aβ) peptides may cause Alzheimer's disease (AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting Aβ have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating Aβ clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Aβ monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating Aβ formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases, β-secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of γ-secretase, the protease that regulates the last metabolic step generating Aβ, have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate α-secretase, the enzyme responsible for the nonamyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of Aβ aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-Aβ approaches in clinical testing, we will know in few years if the Aβ hypothesis of AD is correct.
AB - Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of β-amyloid (Aβ) peptides may cause Alzheimer's disease (AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting Aβ have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating Aβ clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Aβ monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating Aβ formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases, β-secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of γ-secretase, the protease that regulates the last metabolic step generating Aβ, have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate α-secretase, the enzyme responsible for the nonamyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of Aβ aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-Aβ approaches in clinical testing, we will know in few years if the Aβ hypothesis of AD is correct.
KW - α-secretase activators
KW - β-amyloid
KW - β-secretase inhibitors
KW - γ-secretase inhibitors
KW - γ-secretase modulators
KW - Active immunotherapy
KW - Alzheimer's disease
KW - Passive immunotherapy
UR - http://www.scopus.com/inward/record.url?scp=77949768182&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77949768182&partnerID=8YFLogxK
U2 - 10.2174/156720510790274400
DO - 10.2174/156720510790274400
M3 - Article
C2 - 19939231
AN - SCOPUS:77949768182
VL - 7
SP - 40
EP - 55
JO - Current Alzheimer Research
JF - Current Alzheimer Research
SN - 1567-2050
IS - 1
ER -